Dioxins, the aryl hydrocarbon receptor and the central regulation of energy balance

Frontiers in Neuroendocrinology 31 (2010) 452–478

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Review

Dioxins, the aryl hydrocarbon receptor and the central regulation of energy balance

Jere Lindén a,b, Sanna Lensu c,d, Jouko Tuomisto c, Raimo Pohjanvirta a,*

a Department of Food Hygiene and Environmental Health, Faculty of Veterinary Medicine, University of Helsinki, P.O. Box 66, FI-00014 University of Helsinki, Finlandb Department of Veterinary Biosciences, Faculty of Veterinary Medicine, University of Helsinki, P.O. Box 66, FI-00014 University of Helsinki, Finlandc Department of Environmental Health, National Institute for Health and Welfare, P.O. Box 95, FI-70701 Kuopio, Finlandd Faculty of Health Sciences, The School of Pharmacy, University of Eastern Finland, P.O. Box 1611, FI-70211 Kuopio, Finland

a r t i c l e i n f o

Article history:Available online 17 July 2010

Keywords:DioxinsTCDD2,3,7,8-tetrachlorodibenzo-p-dioxinAryl hydrocarbon receptorFood intakeEnergy balanceBody weightWasting syndromeCentral nervous system

0091-3022/$ - see front matter � 2010 Elsevier Inc. Adoi:10.1016/j.yfrne.2010.07.002

* Corresponding author. Fax: +358 9 19157170.E-mail address: [email protected] (R. P

a b s t r a c t

Dioxins are ubiquitous environmental contaminants that have attracted toxicological interest not only forthe potential risk they pose to human health but also because of their unique mechanism of action. Thismechanism involves a specific, phylogenetically old intracellular receptor (the aryl hydrocarbon receptor,AHR) which has recently proven to have an integral regulatory role in a number of physiological pro-cesses, but whose endogenous ligand is still elusive. A major acute impact of dioxins in laboratoryanimals is the wasting syndrome, which represents a puzzling and dramatic perturbation of theregulatory systems for energy balance. A single dose of the most potent dioxin, TCDD, can permanentlyreadjust the defended body weight set-point level thus providing a potentially useful tool and model forphysiological research. Recent evidence of response-selective modulation of AHR action by alternativeligands suggests further that even therapeutic implications might be possible in the future.

� 2010 Elsevier Inc. All rights reserved.

1. Introduction

Dioxins constitute a toxicologically and endocrinologicallyintriguing group of chemicals because they affect most endocrineorgans in laboratory animals. An especially tantalizing and scientif-ically challenging impact highly characteristic of these compounds– but a notably rare outcome of chemical exposure in general – isseverely and perpetually derailed regulation of energy homeostasisand body weight whose manifestations range from inhibition offurther growth to a dramatic body weight loss (dubbed the wastingsyndrome). In this review, we will present new behavioral and bio-chemical findings from dioxin-exposed animals in the context ofcurrent concepts on the central regulatory systems for energy bal-ance. We will first introduce dioxins and briefly outline their majortoxic impacts in laboratory animals and humans (Section 2). Wewill then deal with their molecular mechanisms of action andthe crucial role played therein by a specific receptor protein (arylhydrocarbon receptor; AHR or ‘‘dioxin receptor”) and its main sig-naling pathway (Section 3). Evidence demonstrating the existenceof this signaling pathway in a fully functional composition in thecentral nervous system (CNS) will be provided next (Section 4).The final Section 5 will focus on alterations caused by the most po-tent dioxin, TCDD, in consummatory behaviors and energy balancewith special reference to the wasting syndrome. The biochemical

ll rights reserved.

ohjanvirta).

basis of these alterations will be pursued by elaborating on theinterference of TCDD with the networks, circuits and neurochemi-cals underlying the central regulation of energy balance, of which asuccinct account will also be given.

2. Dioxins as environmental and food contaminants

‘‘Dioxins” are perhaps the most feared group among the persis-tent organic pollutants (POPs). In fact, it is an inaccurate term forrelatively loosely related group of various chemicals, includingpolychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dib-enzofurans (PCDFs), and dioxin-like polychlorinated biphenyls(PCBs). Toxicologically relevant congeners of these have been givena toxicity equivalence factor (TEF value) [484] related to the mosttoxic dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or simply‘‘dioxin”). In addition, respective polybrominated compounds exertdioxin-like activity, as well as some more distant chemicals such aspolychlorinated azoxy-benzenes. The potency of these compoundsvaries widely, as does the sensitivity of animal species and evenstrains or substrains to their toxicity. Furthermore, their toxicityis qualitatively species-dependent [338]. This makes their riskassessment very challenging.

There have been a few dramatic cases of human exposure dueto occupational exposure, accidents, or deliberate poisoning. Themost recent ones are illustrative of the challenges these com-pounds represent to risk assessment. In 1998 two adult womenwere poisoned at their workplace in Vienna by huge doses of TCDD

J. Lindén et al. / Frontiers in Neuroendocrinology 31 (2010) 452–478 453

[143,144]. TCDD concentrations especially in one of them were ex-tremely high, in fact the highest ever measured, 144,000 pg/g inserum fat (equal to a single dose of about 25 lg/kg). She survived,but suffered from severe chloracne lasting for years. Other symp-toms included relatively mild gastrointestinal symptoms and sub-sequent amenorrhea, but abnormal laboratory findings were veryfew [143].

In 2004, then presidential candidate of Ukraine Victor Yush-chenko was deliberately poisoned with a huge dose of TCDD[436]. His TCDD concentration was 108,000 pg/g fat, and after ini-tial malaise and stomach pain the most remarkable symptom wasagain severe chloracne. These two cases indicate that humans arenot likely to be as sensitive as the most sensitive animal species,and that acute toxicity is not the most essential feature of dioxinadverse effects; rather the long-term effects may be of concern.This supports the notion after an industrial accident in Seveso,Italy, in 1976 where thousands of inhabitants were exposed toTCDD after a release of kilograms of TCDD from a pressure tank.High TCDD concentrations up to 56,000 pg/g fat were noted espe-cially in children obviously playing outside and eating local food.The acute effects were limited to about 200 cases of chloracne[280] (the human impacts of dioxins will be addressed in more de-tail in Section 2.6). Because of the unique mechanism of action ofTCDD, however, all aspects of dioxin toxicity are highly interestingin a scientific sense, as a tool to understand animal physiology andbiochemistry.

2.1. Chemistry

There are 75 possible congeners of polychlorinated dibenzo-p-dioxins (PCDD) and 135 possible congeners of polychlorinated dib-enzofurans (PCDF). However, only compounds with so called lat-eral chlorine substitutions at the positions 2,3,7, and 8 (Fig. 1)are specifically toxic, because others do not bind to the aryl hydro-carbon receptor (AHR) and/or are metabolized much faster thanthe 2,3,7,8-congeners. TEF values have been estimated for 17 ofthem (seven dibenzo-p-dioxins and 10 dibenzofurans) having 4–8 chlorine substitutes. Each chlorine substitute in excess of the four

Dibenzo-p-dioxin

10 9

8

7

5 64

3

2

1O

O

2,3,7,8-TCDD

O

O

ClCl

Cl Cl

2,3,4,7,8-PeCDF

O

Cl

Cl

Cl

ClCl

Fig. 1. Structures of dibenzo-p-dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)and 2,3,4,7,8-pentachlorodibenzofuran (2,3,4,7,8-PeCDF).

(2,3,7, and 8) decreases the potency, but by and large the toxic ef-fects remain the same [484].

The 209 PCB-compounds can be divided to three groups (Fig. 2).The four non-ortho compounds having no chlorine substitute inany o-position to the inter-ring C–C-bridge (2,20,6 or 60) are the mostpotent as a group. Among them 3,30,4,40,5-penta-CB (PCB126) isclose to the most potent dioxins in its toxicity [484]. The eightmono-ortho PCBs have some activity (roughly thirty thousand timesweaker than TCDD), and all other PCBs are devoid of a noticeabledioxin-like effect. This is due to the requirement of binding to theAHR: only compounds able to assume a planar (flat) position are ableto bind to the receptor. Only non-ortho compounds are freely rotat-ing along the C–C-bridge, and each o-chlorine makes it more difficultfor the molecule to assume a planar conformation (Fig. 2).

Other groups of planar halogenated molecules have not been gi-ven TEF values, although e.g. some brominated compounds mightdeserve it [484].

2.2. Sources

The sources of PCBs are different from those of PCDD/PCDFs.PCB-compounds were technically excellent oils because they wereresistant to pressure, chemically stable, non-flammable, and elec-trically non-conductive. Therefore they were used from 1930s to1980s for multiple purposes, e.g. in heavy-load hydraulic equip-ment, heat exchangers, electrical equipment, and as componentsin plastic ware. Even after their adverse properties were notedand their production discontinued in most countries in the1980s, these compounds linger on in many products such as elec-trical transformers and plastic materials, and some of the residualPCB ends up to waste incineration or dumps, and then to the gen-eral environment.

PCDD and PCDF compounds were never synthesized except forscientific research, though they are unwanted synthesis side prod-ucts of many chemicals such as PCBs, chlorophenol fungicides andphenoxy acid herbicides. Their major sources are many, mostlydealing with burning processes [374,440]. Any burning will pro-duce dioxins, if chlorine is available, and especially so, if metal cat-alysts such as copper are present. Therefore poorly controlledurban waste incineration used to be one of the most importantsources. This can be technically solved by ensuring high incinera-tion temperature (1000 �C or more) and effective flue gas filtration,and in modern good-quality incinerators dioxins are not a problem[274]. In fact dumpsites as an alternative may be worse, becausesome dumpsite fires are almost unavoidable, and in poor burningconditions the production of dioxins may be high [104,247,390].

Chlorine bleaching of pulp is another example of dioxin produc-tion that has been successfully abated by improving technology.Likewise, most chemical syntheses prone to produce dioxin

Biphenyl

5’6’65

4’4

3’2’3 2

Cl

Cl

Cl

Cl

Cl

3,3’,4,4’,5-PCB

Fig. 2. Structures of biphenyl and 3,30 ,4,40 ,5-pentachlorinated biphenyl (PCB 126).

454 J. Lindén et al. / Frontiers in Neuroendocrinology 31 (2010) 452–478

impurities (production of PCBs, chlorophenols, phenoxy acids, etc.)have been discontinued or technology improved. Examples of theremaining dioxin sources aside from the poor incinerator plantsare steel industries and local burning of solid fuels [18,233,369]as well as recycling of electrical devices [262,500].

2.3. Fate in the environment

Both PCBs and PCDD/PCDFs are highly resistant compounds inall aspects: physical, chemical and biological. They are very slowlybroken down in the environment by ultraviolet radiation and bio-degradation [428]. In the dark they are stable for decades, maybeeven millennia. Because they are extremely poorly soluble to water[8,269], they tend to bioaccumulate to all organic materials, espe-cially to lipids, due to their high lipid–water partition coefficients[268]. There has been an active search for micro-organisms ableto break down PCBs and PCDD/PCDFs, but the success has as yetbeen limited [56,512]. Mammals metabolize these compoundsvery ineffectively and slowly [483]. Therefore they also biomagnifyin the food chain meaning that the higher an organism is in thefood chain, the higher is the concentration. This is clearly seen infish-eating birds and seals which easily collect harmful amountsto their bodies [220]. Humans are at less risk because their dietis not from a single source, even if they are at the top of the foodchain.

2.4. Human intake and levels

Almost all of PCB and dioxin intake is from food of animal ori-gin: milk, meat or fish predominate depending on the countryand the culture [251]. In many countries the daily intake of dioxinsand dioxin-like PCBs is of the order of 100 pg/day, i.e. 1–2 pg/kg/day, in a few countries higher (given as TEQ as are other valuesin this paragraph, see below). Since the half-lives are very long(for e.g. TCDD 7–8 years), the body burden will increase almostover the whole lifetime. Therefore the concentrations may increase5- to 10-fold from age 20 to age 60 [216,322]. In Western Europe,the highest body burdens were found in the 1970s and early 1980s[309], and the trends have been similar in the US [405].

One of the most useful measures of time trends of body burdens isconcentration in breast milk measured over decades [52,77,251,485].In many countries with relatively high exposures the concentrationshave decreased to about one tenth of those in 1970s, and the total TEQconcentrations (TCDD/F + PCB) are now of the order of 10–30 pg/g fat[1,130,252,309,408,460]. The decrease is due to strict emissioncontrols and also to the control of concentrations in food (e.g.[130,252]). In the US young adult female population (age group20–39), the concentration was 9.7 pg/g lipid in 2001–2002 (geomet-ric mean) [322].

2.5. Toxicity equivalents

Because we are dealing with a number of chemicals of differentpotencies, simply adding the amounts or concentrations does notgive useful information on total toxicity. Therefore toxicity equiv-alence factors (TEF) are used. This is mostly but not exclusivelybased on potency (see [484]), and the starting point is TCDD giventhe value of 1. Other compounds are designated with TEF valuesfrom 0.00003 to 1. The amount or concentration of a given com-pound is multiplied by its TEF, and the result is the amount or con-centration equivalent to that of TCDD. These partial equivalents ofcongeners are then added up to make sum toxic equivalent (TEQ)of the mixture. This can be used as a proxy of the total toxicamount of dioxin-like compounds while appreciating that it is aconsensus value based on several assumptions rather than a scien-tific fact [484].

2.6. Toxic effects in humans

This subsection will only deal with toxic effects believed to bedue to binding to the AHR. Non-dioxin-like PCBs may have othereffects based on different mechanisms.

Toxic effects confirmed in humans are, fortunately, relativelylimited. For example, the hallmark effect of acute dioxin toxicityin animals, the wasting syndrome (see Section 5), has apparentlynot been detected in humans to date, although one of the two wo-men exposed to high levels of TCDD in Vienna described above suf-fered from a notable body weight loss [143]. However, this wasassociated with nausea and vomiting, which are atypical of thewasting syndrome in animals [342]. In humans, a classical hall-mark of dioxin toxicity is chloracne. It has manifested after occupa-tional exposure [447], as well as after high acute doses [143,436].Experience from the Seveso accident in 1976 seems to indicate thatchildren are more sensitive to the effects of TCDD, with chloracneat concentrations of less than 1000 pg/g fat [280] while someadults with concentrations of up to 10,000 pg/g fat had no chlor-acne. Even in children very few clinical symptoms and almost nopathological laboratory findings were noted regardless of a maxi-mum concentration of 56,000 pg/g TCDD in serum lipid [280].

The most sensitive effects in humans as well as in experimentalanimals are believed to be developmental effects [79]. In animalsthese occur after single doses of 30–100 ng/kg to the dam[151,201,266]. There are very few data on these at the dioxin levelsprevalent in the general human population. Some mineralizationdisturbances of teeth were noted in 7-year-old children (born in1987), related to their dioxin exposure via breastfeeding [13,14].Enamel defects were found in those Seveso victims who were ex-posed under the age of five [11].

Most other findings are from accidents or occupational settingswith very high intakes (cf. [113,447]). The most dramatic effectswere seen after the so called Yusho and Yu-cheng PCB accidents inJapan 1968 and Taiwan 1979, respectively. The developmental ef-fects included intrauterine growth retardation, hyperpigmentation,neurological dysfunctions, natal teeth, and alterations in sexualdevelopment (for reference see [113]). An interesting finding afterthe Seveso accident was a change in sex ratio towards more girlsborn to those fathers who were exposed to TCDD as children [279].

Other possible health effects include liver problems, changes inlipid metabolism or thyroid function, diabetes, other endocrinedisturbances, immunological effects and cardiac mortality hypoth-esized by the authors to be due to stress responses [447]. There islittle evidence of these at the present exposure levels, and in manycases the evidence is ambiguous even at high exposure levels. Oneof the problems is simultaneous exposure to other chemicals, oftenthe main chemicals containing dioxins as minor impurities.

Cancer is perhaps the most debated issue. While it is clear thatdioxins have carcinogenic potential both in animals and in man, itis unclear whether this is only a high-dose phenomenon basedmostly on tumor-promoting effects of dioxins [98]. The Interna-tional Agency for Research on Cancer classified TCDD as a humancarcinogen in 1997 [186]. A large case-control study found no evi-dence of the correlation of dioxins with soft-tissue sarcoma, one ofthe implied ‘‘dioxin cancers” [466]. In a recent study the mortalityin Baltic Sea fishermen with high dioxin levels was found to belower than in controls [475], and this was not only true of low car-diac mortality which may be due to high intake of omega-3 fattyacids in fishermen, but also of cancer mortality. Only mortalityfrom lymphoid/hematopoietic malignancies was non-significantlyincreased. This might be in line with the Seveso cancer studieswhich have implied an excess of lymphatic/hematopoietic malig-nances, among which excesses of multiple myeloma and myeloidleukemia were also significant in the second most contaminatedzone [78,324].

J. Lindén et al. / Frontiers in Neuroendocrinology 31 (2010) 452–478 455

2.7. Toxicity in experimental animals

In animal studies, a myriad of various toxic effects have beenshown mostly by using TCDD (cf. [40,42,338,462,501]. In addition,there are many biochemical effects such as enzyme induction thatmay not necessarily mean toxic insults but could rather representadaptive responses. Animal toxicity described in hundreds of pa-pers will not be exhaustively dealt with here; instead, the readeris referred to the reviews above.

There are several conspicuous features in the toxicity of TCDD.Even high doses of TCDD or other dioxins do not kill animalsimmediately but in one to several weeks, after substantially re-duced feed intake and severe weight loss of even more than 50%– dubbed the wasting syndrome (see Section 5 for details). Lethaldose levels vary widely among species and strains. The LD50 value(dose killing 50% of animals) for guinea pigs is 1–2 lg/kg and formost rat strains 20–50 lg/kg, but the most resistant Han/Wistar(Kuopio) (H/W) rat strain may tolerate more than 10,000 lg/kg.In the case of mice, the LD50 for most strains ranges from 150 to300 lg/kg, but for a resistant strain, DBA/2, it is about 10 timeshigher. The most resistant mammalian species is the hamster withan LD50 of 1000–5000 lg/kg [338].

The mechanisms of intra-species differences vary, but seem to in-volve the AHR. The AHR is a ligand-activated transcription factorwhich regulates the transcriptional activities of numerous genesincluding CYP1A1, CYP1A2 and certain other drug-metabolizing en-zymes. It will be discussed in detail in Section 3. In the DBA/2 mousestrain, the affinity of dioxins to the AHR is decreased due to a muta-tion in the ligand-binding domain of this receptor (cf. Fig. 3), easilyexplaining the sensitivity difference as compared with most otherstrains [348]. In contrast, in H/W rats the binding of TCDD to theAHR as well as the binding of the receptor complex to the DNA occurnormally (see Section 3.1), but alternative splicing in the transacti-vation domain of the receptor protein probably makes the receptorineffective at initiating transcription of some genes but not all[345]. This causes a very peculiar difference as compared with thesensitive-resistant mouse pairs. In the resistant mouse all responsesare hampered about to the same extent, but in H/W rat someresponses are not changed at all (typically induction of CYP1A1and CYP1A2 enzymes) while other responses are drastically weak-ened (e.g. lethality, increase of bilirubin levels) [338,426,472]. Thisencouraged our group to divide dioxin responses to two types, dioxinI responses not sensitive to alterations in the transactivation domain(Fig. 3), and dioxin II responses highly sensitive to them [426].

The mechanism for the different sensitivity to TCDD lethalityand other type II responses between the strains is not clear, butit may be envisioned that ligand-bound AHR, acting as a transcrip-tion factor, up- or down-regulates many genes, and some of these

Fig. 3. Major functional domains of the AHR. The approximate locations of theregions responsible for DNA binding, nuclear translocation and export (NLS andNES, respectively), ligand binding (depicted with red TCDD molecule), HSP90binding, heterodimerization as well as transactivation are shown. The PAS domaincomprises two subdomains, A and B. The transactivation domain has at least threesubdomains, but only one of them, Q-rich, is illustrated.

are sensitive to the changes in the transactivation domain, someare not. Indeed, rat AHR seems to be involved in the regulationof hundreds of genes, and transcriptomic studies reveal numerousdifferences in up- or down-regulation between the strains ([459]).Furthermore, the number of hepatic genes affected by TCDD issmaller in H/W rats than in TCDD-sensitive strains [124].

The wasting syndrome is associated with a variety of changes inmetabolism, but it has been difficult to explain lethality or wastingby these changes (cf. [338]). Acute toxicity is also qualitatively dif-ferent among species, e.g. there is severe liver necrosis in the rabbitbut not in most other species, and there seem to be differences inendotoxin responses, edema, cytokines and inflammation betweenrats and mice [338].

Various pleiotropic responses are typical of dioxin toxicity:there may be both hyperplastic or proliferative responses andhypoplastic or atrophic responses [338]. Hyperplasia of the seba-ceous glands is seen in some species but not in most, even if chlor-acne is typical in human poisoning [42]. Thymic atrophy is aconsistent finding. Some effects on the immune system are ob-served at remarkably low dose levels. It is not fully clear if the mostsensitive changes are related to toxicity or if they are adaptive, butincreased susceptibility towards infections has been noted at quitelow dose levels [42].

The most sensitive effects may be developmental effects, andthese are also the basis of the most recent risk assessment [79].In mice typical malformations are cleft palate and hydronephrosisat doses not toxic to the dam. In rats various adverse effects of sex-ual development [151,266] are more typical, as well as distur-bances of tooth development [12,201]. As mentioned above,many of these developmental effects have in some studies been re-ported to occur at single doses as low as 30–100 ng/kg to the ratdam. However, other studies have found higher thresholds (re-cently reviewed in [31]).

Dioxins are clear multisite carcinogens at doses low in absolutesense but relatively high as compared with general toxicity [98].Much of the cancer risk assessment has been based on a singlerat study [219], demonstrating liver tumors in female rats at lowerdoses (10 ng/kg/day TCDD for 2 years) than most other studies.Toxic hepatitis was also found in animals with tumors, and be-cause there is no evidence of direct genotoxicity of TCDD, non-genotoxic or promoting mechanisms are favored [98]. When differ-ently sensitive Long-Evans (Turku/AB) (L-E) and H/W rat substrainswere compared in a 3-month tumor promotion study, there was adifference of almost two orders of magnitude, and in both strainstumor promotion was associated with signs of liver toxicity[486]. Such findings suggest that carcinogenicity is secondary totoxicity, possibly due to oxygen radical formation or inflammation.

3. Intracellular messenger of dioxins: the AHR

The biological effects of dioxins in the body critically depend on acytosolic protein, the AHR. The evidence supporting this conclusionis multilevel. For example, the toxicity of dioxin congeners correlateswith their binding affinity to the AHR [347,394]. In inbred C57BL/6Jand DBA/2J mouse strains as well as in C57BL/6J mice congenic at theAh locus, a 10-fold difference in binding affinity of the AHR to TCDD isassociated with a sensitivity difference of a similar magnitude inmost of the toxic and biochemical impacts caused by TCDD[41,67]. A similar correlation exists among bird species [198]. Asdescribed above, a substrain of rat, H/W, is up to 1000-fold moreresistant to TCDD lethality than sensitive rat (sub)strains, and thisresistance is mainly attributable to a mutation in its AHR structure[332,338,345,472]. The most definitive evidence comes from studieswith AHR knockout mice, which have proved to be unresponsive toall major effects of TCDD [115,278,491].

456 J. Lindén et al. / Frontiers in Neuroendocrinology 31 (2010) 452–478

The AHR belongs to basic Helix–Loop–Helix/Periodic, AHR nucle-ar translocator, Single-minded (bHLH/PAS) proteins which haveimportant roles in protection against hypoxia, in regulation of neuraldevelopment, in generation and maintenance of circadian rhythmsand as transcriptional partners and co-activators [129,211]. Func-tionally, the AHR resembles the nuclear receptors (in which it wasinitially categorized) acting as a ligand-activated transcriptionfactor. In response to activation by dioxins, the AHR signaling path-way modifies the expression levels of numerous genes. The bestcharacterized of these at the molecular level is the induction of thegene for a Phase I drug-metabolizing enzyme, CYP1A1 (for recentreviews, see [28,129,314]).

3.1. The canonical AHR signaling pathway as elucidated for theCYP1A1 gene (Fig. 4)

In the dormant state, the AHR resides in the cytosol in a proteincomplex also containing a dimer of Heat Shock Protein 90 (HSP90),AHR-associated protein-9; also known as XAP2 or AIP (ARA9) andp23 [28,89,265,302]. These chaperone proteins stabilize the AHRmaintaining it in a conformation which is unable to enter the nu-cleus but optimal for ligand binding [203–205,329]. Upon ligandbinding, the AHR undergoes a transformation in which the N-ter-minal nuclear localization signal is exposed and recognized byimportin-b, and the protein complex translocates into the nucleus[187,328,379]. Recent evidence suggests that CaMKs (Ca2+/calmod-ulin-dependent protein kinases) and phosphodiesterase type 2Amay be required for the translocation step [87,282]. The AHR thendissociates from the chaperones and heterodimerizes with anotherbHLH/PAS protein, ARNT (AHR nuclear translocator) [134,377]. TheAHR/ARNT dimer binds to the DNA within the major groove of theDNA helix at specific sites, dioxin response elements (DREs, alsoknown as xenobiotic response elements or AHR elements) locatedupstream of the proximal promoter region of the CYP1A1 gene andharboring the minimal consensus core sequence 50-A/TNGCGTG-30

[90,126,230,444,495]. In these enhancers, ARNT binds to the E-boxhalf-site GTG and AHR to 50 sequence immediately adjacent to it[23,445]. DNA binding is followed by interactions of the AHR/ARNTdimer with transcriptional coregulators such as steroid receptor co-activator 1 (SRC-1) [30,234], steroid receptor co-activator 2 (SRC-2)[450], nuclear receptor co-activator 2 (NCoA2) [30,174], nuclearreceptor co-activator 3 (NCoA3) [30], CREB binding protein (CBP)/p300 [30,217,461], receptor-interacting protein 140 (RIP140)[236], Brahma/Switch 2-related gene 1 (BRG-1) [450,493], thyroidhormone receptor/retinoblastoma interacting protein 230 (TRIP230)[29] and silencing mediator for retinoic acid and thyroid hormonereceptors (SMRT) [304,391,505]. Which coregulators are recruiteddepends on cellular context. Especially important appear to be thosecofactors that possess intrinsic histone acetyltransferase activitysuch as p300, CBP, SRC-1 and SRC-2 since they can relax the chroma-tin structure [30,174,421]. H4 or H3 histone acetylation at theCYP1A1 promoter is then associated with recruitment of RNA poly-merase II to the proximal promoter and launching of CYP1A1 mRNAtranscription [30,273]. AHR activity is terminated by nuclear exportof the receptor [86,187] and by its ubiquitin-mediated degradationby the 26S proteasome [86,263,384].

3.2. Other genes regulated by the AHR

In addition to CYP1A1, dioxin-activated AHR induces otherPhases I and II drug-metabolizing enzymes in liver includingCYP1A2, CYP1B1, CYP2S1, CYP2A5, ALDH3, GSTA1, UGT1A1,UGT1A6, UGT1A7 and NQO1, presumably in most cases by thesame general mechanism [19,27,28,55,229,231,311,448,525,526].However, for the CYP1A2 gene there may be remarkable species-specific variation in DRE location [316] as well as in DRE structure

and in the mode the AHR-ARNT heterodimer binds to it [433]. Fur-thermore, the contribution of Nrf2 (erythroid 2-related factor 2)appears to be required for induction of UGT1A6, NQO1 and GSTA1[264,523], and ALDH3 may be also be regulated by mechanismsdifferent from the canonical AHR signaling pathway [101,227]. Tis-sue-dependency of the induction phenomenon varies among theenzymes: While CYP1A1 responds to dioxins in a wide variety oftissues, induction of CYP1A2 is mainly confined to liver and nasalepithelium [146,259,503]. Due to its ability to bind dioxins, in-duced CYP1A2 can modulate their kinetics by accumulating themin the liver [207,349,350,490]. There is a nice correlation amongdioxins and related compounds between their potency to elicit he-patic CYP1A1 induction and to cause major toxicities such as im-mune suppression, body weight loss and thymic atrophy [392].However, differences among species or strains in their sensitivitiesto the acute toxicity of dioxins are generally not reflected in theirsensitivities to enzyme induction, and thus enhanced activity ofcytochrome P450-associated mono-oxygenases is not believed tobe causally related to, or play any major direct role in, dioxin tox-icity ([138,311,333], although there are some contradictory datafrom mice [431,482].

Apart from drug-metabolizing enzymes, TCDD exposure modi-fies the expression of a large number of other genes, presumablyby a similar mechanism. For example, in adult mouse or rat liver,hundreds or even thousands of genes are affected [49,123,124,401,459]. A somewhat surprising finding has been that there ap-pears to be conspicuously little overlap in the patterns of targetgenes across species or among tissues within a given species [48–50,63,212,361]. Frequently, gene expression is repressed by TCDDinstead of being induced. Next to nothing is known about the mech-anism(s) of this gene silencing [381] but at least in adult rats, it doesnot appear to involve micro-RNAs [281]. Epigenetic regulationthrough DNA methylation or histone modification may, however,be at play [375].

One of the genes induced by TCDD plays a role in AHR regulationby forming a feedback loop: AHR repressor (AHRR) [277]. It inhibitsthe transcriptional activity of dioxin-activated AHR by a mechanismwhich is incompletely understood at present but which may involveSUMOylation of certain lysine residues in the C-terminal repressiondomain of the AHRR [318] (reviewed in [159]). The effect of the AHRRis not fully specific to the AHR but extends to a structurally relatedprotein, hypoxia-inducible factor signaling [199].

3.3. Non-canonical signaling pathways

The AHR has been shown to interact with other signal transduc-tion pathways including nuclear factor kappa B (NF-jB) [206,214,321,455,488], protein tyrosine kinases and EGFR (epidermal growthfactor receptor) [21,73,110,443], p53 and pRb (retinoblastoma)[108,140,319], HIF-1a (hypoxia-inducible factor 1a) [65,177], TGF-b (transforming growth factor b) [131,190,382], Nrf2 (nuclear factorerythroid 2-related factor 2) [423,523], cAMP/PKA (cyclo-AMP/pro-tein kinase A) [88,95,312,489] and MAPKs (mitogen-activated pro-tein kinases) [239,320,449,499] (for reviews, see [62,156,359,362,458]). Importantly, this crosstalk appears to often occur by mecha-nisms distinct from the canonical pathway such that DRE bindingor heterodimerization with ARNT is not involved. Both the classicaland alternative pathways can also jointly contribute to the final out-come as in the case of one of the most exhaustively examined pro-teins interacting with the AHR, the estrogen receptor (ER)(reviewed in [272,446]). Dioxin-activated AHR interferes with ERsignaling at multiple steps: It causes transcriptional repression ofER [456,457], may reduce ER ligand levels [438], interferes with ERsignaling through inhibitory DREs [393], recruits ER to establishedAHR-regulated genes (where ER may enhance AHR function butAHR diverts it from estrogen target genes) [273,507], competes with

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ER for ARNT as a partner or co-activator [389], and can target ER forproteasomal degradation by acting as an E3 ubiquitin ligase [313].

One of the earliest changes caused by TCDD in vitro is an in-crease in intracellular Ca2+ concentration [43,164,360]. This ef-fect may have important sequelae such as activation of CaMKswhich appears to converge on the canonical pathway at theAHR nuclear translocation phase [282]. Furthermore, it has beenproposed to lead to elevated levels of Cox2 mRNA and thus to aninflammatory response by two distinct alternative nongenomicpathways whose selection depends on cellular context [94–96,271,413,414].

Although it has been well-established that the AHR itself isindispensable for virtually all aspects of dioxin toxicity examined[15,185,255,256,278,306,454,491], the contribution of the alterna-tive AHR signaling pathways in the diverse biochemical and toxiceffects of dioxins is as yet poorly explored. Two characteristic ter-atogenic impacts of TCDD in mice are hydronephrosis and cleft pal-ate. It was recently shown that hydronephrosis induced in mousepups by lactational exposure to TCDD appears to be criticallydependent on Cox2 [305] suggesting a key role for the alternativepathways. However, a systematic approach by means of transgenicmouse models carried out in Christopher Bradfield’s laboratory hasconvincingly demonstrated the supremacy of the canonical path-way in the mediation of the major outcomes of dioxin exposurein vivo. Mice in which either the nuclear translocation or DRE bind-ing is defective are refractory to both adaptive and toxic effects ofTCDD (CYP1A1 induction, hepatotoxicity, thymic atrophy and ter-atogenesis) [57,58]. An especially noteworthy observation in thesestudies was that hydronephrosis elicited by in utero exposure toTCDD was absent in mice whose AHR is unable to bind to the DREs.Either this lesion evolves by different mechanisms depending ondevelopmental stage or in this case induction of Cox2 occurs viathe classical pathway. Furthermore, mice which express reducedlevels of ARNT exhibit CYP1A1 induction but not thymic atrophyor hepatotoxicity [492]. Interestingly, all these mouse models withimpaired canonical AHR signaling also manifest the developmentalphenotype of AHR-deficient mice, foremost persistent ductusvenosus and a small liver (see below). This implies that both theeffects triggered by binding of a high-affinity ligand (TCDD) tothe AHR and the major endogenous functions of the AHR are med-iated by one and the same, canonical, signaling pathway.

3.4. Phylogeny of the AHR

Evolutionarily the AHR appears to be an over 500-million-year-old protein occurring in all vertebrates [59,160]. Ancient homologsof the AHR have even been discovered in invertebrates such asnematodes (C. elegans) [356] and insects (spineless in D. melano-gaster) [100]. However, a distinctive feature of these primitiveAHR forms is their inability to bind dioxin or other ligands of themammalian AHR [59,161,356]. In spite of this incapability, theyhave been shown to play important developmental roles in neuro-nal differentiation and regulation of feeding-related aggregationbehavior (C. elegans) [183,365,366] or in regulation of normal mor-phogenesis of the leg or antenna and bristles (D. melanogaster)[100,109]. A recent study provided direct experimental evidencethat the drosophila AHR homolog is constitutively active [232].

While mammals have only a single AHR gene, fish and birds areendowed with at least two distinct AHR genes (for reviews, see[157,158,160]). Nevertheless, splicing variants of both the AHRand ARNT have been found to exist in rats [226,345].

3.5. Molecular structure of the AHR in relation to its function

The AHR has a modular structure (Fig. 3). The ligand-bindingdomain is located in the middle region and exhibits variation in

primary structure that is functionally reflected in inter- and intra-species differences in sensitivity to dioxin toxicity. For example, sen-sitivity differences between C57BL/6 and DBA/2 mouse strains aswell as those among bird species derive from polymorphisms atone or two amino acids in the ligand-binding domain resulting inaffinity differences in dioxin binding [53,167,198,348,398]. Lowaffinity of amphibian AHR to TCDD may also account for the insensi-tivity of frogs to dioxin toxicity [26,245]. At the N-terminal end, thebasic region is responsible for DNA binding [22,127] while the HLHmotif constitutes the primary interface for heterodimerization towhich the PAS domain confers specificity [257,351]. The N-terminalend further contains structures required for HSP90 binding as well asfor nuclear entry and exit [80,127,187,323]. At the C-terminus, theAHR carries a large transactivation domain consisting of interactingsubunits one of which is a glutamine-rich subdomain [188,192,235,388,432,496,502]. The transactivation domain is intimately in-volved in the interplay with co-regulatory proteins and general tran-scription factors [234,388,493,496], and influences the intracellularlocalization of the receptor [371]. The C-terminal structure of theAHR can also be a key determinant of dioxin sensitivity being sub-stantially altered in the most TCDD-resistant laboratory animals,hamsters and H/W rats [225,314,332,472,486]. However, in contrastto alterations in the ligand-binding domain, remodeling of the trans-activation domain seems to result in a response-selective modula-tion of dioxin sensitivity [314,332].

3.6. Activation of the AHR

The best-understood way of AHR activation is by ligand binding.In addition to dioxins and other halogenated aromatic hydrocar-bons, polycyclic aromatic hydrocarbons (PAH compounds) such asbenzo[a]pyrene and 3-methylcholanthrene constitute another largegroup of toxicologically important environmental contaminantswhich can bind to the AHR [39,47,373]. Although the intrinsic affin-ity of PAHs to the receptor does not necessarily lag far behind that ofTCDD, their potency in bringing about the adaptive enzyme induc-tion response is several orders of magnitude lower, and they donot elicit an identical pattern of toxicities (e.g. wasting syndrome)to that of dioxins [346,347,380]. One of the main reasons for this dis-crepancy is believed to be more persistent receptor binding by TCDDdue to its slower metabolic inactivation compared with PAHs[47,380]. The same explanation also applies to a high-affinity ligandof dietary origin, indolo(3,2-b)carbazole, which appears to bemetabolized too rapidly to cause AHR-mediated toxicity [334].

The ligand-binding domain of the AHR is not highly selectiveregarding the molecular properties of the ligands (for review, see[91]). Both exogenous and endogenous compounds as diverse asflavonoids, 7-ketocholesterol, tryptophan and tryptophan metabo-lites, bilirubin, indirubin, indigo, fused mesoionic heterocycles, andarachidonic acid metabolites such as lipoxin A4 can bind to thereceptor (albeit at varying avidities) and function as either agonists,partial agonists or antagonists [5,7,44,121,136,168,307,325,330,402,403,427,528]. The potency of a compound as a modulatorof AHR action may vary among species [121,171,530]. There is alsoevidence that the pattern of effects mediated by the AHR may de-pend on the ligand, on species from which the receptor originates,or on ligand � receptor interaction, thus providing scientific groundfor the development of selective modulators of AHR action in the fu-ture [122,174,295–297,315,529].

It is possible that ligand is not a prerequisite for AHR activation.For example, certain carotenoids and benzimidazole derivativessuch as omeprazole can induce CYP1A1 in some species in anAHR-dependent manner, but apparently fail to bind to the AHR[85,105,150,248,400]. Similarly, in cell cultures CYP1A1 has beenfound to be inducible by hydrodynamic shear stress [290,291]and by certain heavy metals [107]. Moreover, the AHR has been

1.

2.

Ca2+Cox2 mRNA

Phase I & II DMEs

AHRR

Toxicity genes

mRNA for:

3.

APP mRNA6.

5.

Ubiquitin-26Sproteasome

4.

E3 ubiquitin ligase complex

ER β-catenin

7.

Fig. 4. A schematic and simplified diagram of some salient features of AHR signaling pathways. The canonical pathway is depicted with solid black arrows, alternativepathways with dashed black arrows, and an intersection of these two distinct but linked signal transduction routes with a solid red arrow. The blue bars represent the AHR,light red bars ARNT, green bars ARA9, yellowish brown bars HSP90 and the bright red ovals p23. Dioxin binding to the AHR (1.) leads to its translocation into the nucleus (2.),heterodimerization with ARNT and binding to the DNA at DREs with ultimately modulating expression levels of target genes (3.). One of the gene products elevated by thismechanism is AHRR which forms a feedback loop by inhibiting AHR action. The AHR is finally degraded by the ubiquitin–proteasome system (4.). AHR activation can alsorapidly increase intracellular Ca2+ concentration (5.) which in turn may (through intermediate steps not shown) ultimately result in augmented Cox2 gene expression.Elevation of Ca2+ activates CaMKs which appear to have a critical role in the translocation of the AHR. Two further examples of effects mediated by the AHR via non-canonicalpathways are suppression acute-phase proteins (6.) which does not involve DNA binding, and degradation of e.g. ER and b-catenin [202] by acting as an atypical E3 ubiquitinligase (7.).

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reported to be activated by a high glucose concentration [82].However, it is also possible that the current methods employedfor analysis of AHR ligand binding are not sensitive enough to re-veal a very weak association between the AHR and either the com-pound studied or some endogenous ligand (e.g. arachidonic acidmetabolite or low-density lipoprotein in the case of the shearstress [275,292]). Indeed, involvement of the AHR in the regulationof a number of essential physiological phenomena in the body (seebelow) strongly suggests the existence of a high-affinity endoge-nous ligand (or ligands) for the receptor. Although tryptophanmetabolites in particular have attracted attention in this respect[169,294,303,509], the issue remains unresolved at present.

3.7. Physiological functions of the AHR

AHR-deficient mice have proved to be a highly fruitful model inassessing the role of the AHR in the development of organs and inphysiological functions outside of, and beyond, xenobiotic bio-transformation. These knockouts have independently been gener-ated by 3 laboratories [114,278,407], and their phenotypes haveboth common and distinctive features [240]. One of the most con-sistent findings has been a 25–50% reduction in liver size whichmay result from persistent ductus venosus and thereby from a por-tocaval shunt [165,241,242], or from augmented apoptosis due toelevated levels of TGF-b [147,527]. Relevant to this, angiogenesisin the AHR-deficient mice has been reported to be impaired by amechanism that seems to involve TGF-b [385]. The AHR-null micealso display a slightly slower growth rate compared with wild-typemice for the first few weeks of life [114,278,407]. In addition to theliver, the development of a number of other organs and tissues isinfluenced by the presence or absence of the AHR including heart,spleen, thymus, kidneys, lungs, salivary glands, skin, testes, ante-rior and dorsolateral prostate, seminal vesicles, epididymides, ova-

ries, and, evidently, ventral telencephalon [116,172,255,256]. Inadult mice, the AHR status modulates the expression of severalhundred genes both in liver and in kidney [48,459]. AHR knockoutmice are either hypertensive or hypotensive depending on the alti-tude they are housed [261], and they may be prematurely affectedby age-related degenerative changes [116] leading to a shortenedlife-span [176]. Furthermore, they exhibit reduced fertility [4] atleast in part due to impaired conversion of testosterone to estradiolby ovarian P450 aromatase (Cyp19) [20]. They are also hypersensi-tive to bacterial endotoxin (lipopolysaccharide) [20,214,419,452]as well as having some other less pronounced immune alterations(reviewed in [111,441]).

4. AHR and the CNS

In vitro studies have implied that the degree of AHR expressionmay influence neuronal function. Reduction of AHR levels bymeans of small interfering RNA has been shown to reduce N-methyl-D-aspartate (NMDA) excitotoxicity while augmentingNMDA-induced brain-derived neurotrophic factor expression incortical cells [253]. Over-expression of AHR in the undifferentiatedmurine neuroblastoma Neuro2a cell line, in turn, was reported toinduce catecholaminergic differentiation in them [10].

4.1. Expression of principal molecules of the AHR signaling cascade inthe CNS

The AHR itself as well as other key proteins of the canonicalAHR signaling pathway are expressed from early stages on in themammalian CNS. For example, in mouse embryos both AHR mRNAand protein were present in high concentrations in the neuroepi-thelium of the developing brain at gestational days (GD) 10–11but then started to diminish with only regional, low levels being

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expressed after GD12 [2]. Regarding ARNT in mice, in situ hybrid-ization revealed its mRNA to be highly expressed in the neuroepi-thelium of neural tube at GD9 and especially in neocortical andtectal neuroepithelium thereafter, but overall its levels tended todecline with differentiation of neuronal structures; in hypothala-mus, a strong signal was recorded at GD11 and GD15 [9,189]. ARNTprotein on the other hand was highly expressed in neuroepithe-lium between GD10 and GD12.5 but decreased thereafter in neuralstructures by GD15 [3,434]. Both primary cortical astrocytes frompost-natal day 1 and primary cortical endothelial cells from wean-ling C57BL/6 mice yielded a positive signal in immunocytochemi-cal analysis of AHR protein [120]. When cerebellar AHR andARNT protein expressions were monitored by Western blotting inC57BL/6J mice from birth to adulthood, AHR proved to be presentat all time-points and ARNT from post-natal day 3 on [508].

The perinatal expression profiles of hypothalamic AHR andARNT mRNAs were studied by semi-quantitative RT-PCR in Spra-gue–Dawley rats. AHR mRNA was found to rise steadily from thestart of the study (GD16) to birth and then retain that level tothe last time-point of analysis (post-natal day 15). ARNT mRNA,in contrast, stayed at a constant concentration throughout theobservation period [357]. In another study on 3-day-old rat pups,AHR proved to be expressed in virtually all GABAergic neurons inthe preoptic area [166].

In adult C57BL/6J and DBA/2J mice, AHR mRNA expression levelin brain was similar to that in liver and about 10-fold lower than inthe tissue displaying the highest expression, lung [250]. In the caseof AHRR mRNA, the highest concentrations among the nine tissuesexamined in C57BL/6 mice were found in the brain and heart; inAHR-deficient mice these concentrations were two orders of mag-nitude lower implying a key regulatory role for the AHR [34]. In animmunohistochemical study of the adult Balb/cX129SV mousebrain, AHRR-immunoreactivity was recorded in nuclei of neuronsall over the hypothalamus with the greatest intensity in the arcu-ate nucleus (ARC); outside of the hypothalamus, strong stainingwas seen in the hippocampus and cortex [117].

AHR and ARNT mRNAs are also widely expressed in adult ratbrain [182,195,326]. The presence of their proteins has furtherbeen confirmed by immunoblotting [237]. Although an early studyfailed to detect AHR mRNA in the rat hypothalamus, subsequentstudies have convincingly demonstrated that AHR, ARNT and AHRRare all expressed at this site [182,224] with especially high levels ofAHR and ARNT occurring in caudal ARC [326]. In the suprachias-matic nucleus (SCN), AHR mRNA proved to exhibit circadian fluctu-ation with only slightly smaller amplitude than that for mRNA ofthe clock gene Per1 [293]. The hypothalamus exhibited pro-nounced DRE binding in the rat being second only to cerebellumof the seven brain regions examined [237]. AHR or ARNT mRNAlevels in rat brain do not seem to be influenced by TCDD treatmentin contrast to those of the AHRR which are rapidly (within hoursafter exposure) elevated [182,224].

In human brain, the expression level of AHR mRNA was lowcompared with heart, lung, liver and especially placenta [93,103].An RT-qPCR analysis of adult human samples revealed AHR mRNAexpression to be 2.7 times higher in brain microvessels than in thecortex suggesting preferential expression in the blood–brain bar-rier [84]. In support of this view, CYP1B1 was also highly expressedin the blood–brain barrier. CYP1B1 mRNA represented over 80% ofall the CYP mRNAs detected and its levels were 14 times as high inthe microvessels as in the cortex. The presence of CYP1B1 proteinwas further confirmed by Western blotting [84].

4.2. Induction of drug-metabolizing enzymes in the CNS by TCDD

As functional evidence of a fully integrated AHR signal trans-duction system in the CNS, the classic adaptive response to TCDD

exposure, induction of Phases I and II drug-metabolizing enzymes,has been well documented to occur in various regions of the rodentbrain at mRNA, protein and enzyme activity levels [66,179,181,182,224,476]. In Sprague–Dawley rats, a non-lethal dose of10 lg/kg TCDD brought about a fairly uniform induction of CYP1A1mRNA throughout the brain 1–28 days after exposure. The basallevels amounted to 15–90% of those in liver, but the inductionresponse was much weaker in the CNS [182]. On the other hand,10 days after 5 or 50 lg/kg TCDD to dioxin-sensitive L-E and diox-in–resistant H/W rats, certain regions of the brain (olfactory bulband mid-brain + thalamus) exhibited induction in CYP1A1 activity(measured as EROD [ethoxyresorufin O-deethylase] activity)whose magnitude was almost comparable to that measured inthe liver [476]. Interestingly, in the hypothalamus of these tworat strains not only CYP1A1 but also CYP1A2 mRNA (whose induc-tion exhibits high tissue specificity) was found to be rapidly andpersistently induced by 50 lg/kg TCDD with the magnitude ofCYP1A2 (but not of CYP1A1) induction correlating with TCDD sen-sitivity of the strains [224]. Treatment of Sprague–Dawley ratswith another AHR agonist, b-naphtoflavone, also led to inductionof both CYP1A1 and CYP1A2 mRNAs in various regions of the brain[406]. After b-naphtoflavone treatment, CYP1A1 immunoreactivityand catalytic activity appeared to largely localize in choroid andarachnoid membranes [288].

As to individual cell types in the CNS, CYP1A1 and CYP1B1induction response to TCDD has been reported in mouse primarycerebellar granule neuroblasts [508] and in mouse vascular endo-thelial cells; in mouse astrocytes, CYP1B1 but not CYP1A1 was in-duced [120].

Thus, there is little doubt that a fully functional AHR signalingcascade is present in the CNS, evidently also in humans, and ableto mount an induction response to dioxin exposure.

5. Alterations in consummatory behaviors and in centralregulatory mechanisms of energy balance in dioxin-exposedlaboratory animals

In experimental animals, the acute toxicity of dioxins is typifiedby a peculiarly delayed occurrence of mortality preceded by a dra-matic body weight loss. Although this phenomenon has beenknown for over three decades, its biochemical basis has remainedelusive. However, the potency of TCDD and some other dioxins toirreversibly and fatally suppress the numerous and redundant sys-tems existing in the body to secure one of the most vital functions,adequate food intake, as well as to perpetually derail the controlmechanisms for body weight maintenance implies that resolutionof the pathogenesis of the wasting syndrome might cast new lighton the key factors of energy balance more generally. We have pre-viously reviewed the early data on the influence of TCDD on theCNS, feeding behavior and energy balance [338,478]. In the presentreview, we will mainly focus on more recent findings on alterationscaused by dioxins in consummatory behaviors and on the currentunderstanding of their biochemical basis, but will also outline thesalient facets established previously to help the reader composethe full picture.

5.1. The wasting syndrome

Dioxin exposure causes a dramatic reduction in feeding and aconsequent decline in body weight in exposed animals. This phe-nomenon is known as the wasting syndrome and it is a ratheruncommon manifestation of chemical toxicity in general. A charac-teristic feature of acute dioxin toxicity is that lethality is delayedand preceded by a progressive body weight loss which occurs evenafter a single administration. Death does not ensue until 1–8 weeks

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after exposure with the time course depending on dose as well ason sensitivity of the animal [42,347]. At lethal doses of dioxin, thehypophagic animals can lose over 50% of their body weight beforedeath [338,416,417]. In addition to mice and rats, also other animalspecies such as hamsters and guinea pigs have been reported tosuffer from hypophagia after dioxin exposure although at widelydifferent doses [137,170,209,317]. Despite the fact that TCDD isan extremely potent compound in reshifting body weight, thewasting syndrome has attracted surprisingly little research inter-est. Because of the extensive research efforts put on elucidatingthe mechanisms of obesity and the physiological regulation of en-ergy homeostasis, the resolution of the pathogenesis of the wastingsyndrome would be important not only toxicologically but alsophysiologically.

5.1.1. Relationship with TCDD lethalityThe reduction of body weight has been shown to primarily re-

sult from hypophagia in rats, mice and guinea pigs [209]. Never-theless, TCDD-treated rats do not appear to suffer from nausea[342]. It is also important to note that neither gross malabsorptionnor increased energy expenditure seem to contribute substantiallyto the wasting [354,416,418]. Therefore, our focus in this sectionwill be centered in factors regulating energy intake and bodyweight. Depletion of energy stores in consequence of hypophagiais a major cause of death in dioxin-exposed rats as evidenced bya similar life-span in pair-fed controls [75,498]. However, the factthat force-fed rats [135] and guinea pigs [180] do not lose weightbut still succumb at approximately the same time after TCDDadministration indicates that other mechanisms must also be atplay.

5.1.2. Dietary modulation of the wasting syndromeWhether nutritional obesity, forced feeding or different diets

could diminish or postpone the wasting syndrome was studied inour laboratory using TCDD-sensitive L-E and TCDD-resistant H/Wrats of both sexes [468]. L-E rats having free access to a high-en-ergy diet survived longer after TCDD exposure than rats on a regu-lar diet. The type of diet or feeding protocol was found to affectsurvival: rats on a liquid, high-fat diet (force-fed by gavage) suc-cumbed earlier than rats fed the regular feed (either a fixedamount or ad libitum) or a balanced liquid feed. In fact, it has beenshown by several groups that fat seems to be an unfavorablesource of energy after TCDD exposure [298,299,473]. A balanced li-quid diet (force-fed) prevented weight loss in L-E males following alethal TCDD dose, 50 lg/kg, but still none of the exposed rats sur-vived and the time to death was similar to that in their free-feedingpartners [468]. Obesity, high-energy diet or forced feeding did notprevent weight loss in resistant H/W rats, treated with a high butsublethal dose of TCDD. Although the body weights of H/W ratswere higher on a high-energy diet than on the regular diet,TCDD-treated rats still maintained their weights at a lower levelthan their controls [468]. Taken together, it seems that whereasTCDD lethality cannot be prevented by parenteral nutrition orforce-feeding in rats [135,468] or in guinea pigs [180], the typeof diet affects the severity of TCDD-induced body weight loss inexperimental animals [298,299,468].

A puzzling and totally unexpected outcome appeared in a re-cent study in female C3H/HeN mice that harbor a high-affinityAHR for TCDD. In mice kept on a high-fat diet, repeated exposureto 100 lg/kg TCDD every 2 weeks for a period of 8 weeks resultedin a significantly accelerated body weight gain compared with vehi-cle-treated mice on the same diet. By the end of the experimentalperiod, the mice treated with this dose of TCDD weighed 46% morethan controls on the high-fat diet. In lower exposure groups (1 or10 lg/kg), body weight gain did not deviate from that in controlsand the same was true of all TCDD-dosed groups fed a standard

diet [531]. Although extremely rare, this response opposite towasting is not entirely without precedent: 3,4,30,40-tetrachlorobi-phenyl, a co-planar PCB congener (i.e. an AHR agonist), was foundto cause obesity in Skh:HR-1 mice [363]. However, no cases ofobesity provoked by TCDD or related compounds have so far beenreported in species other than the mouse.

5.1.3. The wasting syndrome and reduced body weight set-pointOnly a single administration of TCDD is needed to elicit the

wasting syndrome because of the sluggish biotransformation andelimination of TCDD in laboratory animals [137,162,344,497]. Dur-ing the first few days after exposure, food intake typically takes aprogressive downhill course leading to weight loss, but the ex-posed animals do not usually show a total refusal of feeding. Atsublethal doses, the animals resume feeding and gaining weightin 1–2 weeks [338,416,417]. Supralethal doses do not much short-en the time to death. In both rodents and nonhuman primates alethal dose leads to death by 8 weeks [42]. Sublethal doses maycause a permanently stunted growth, decreased feeding [340,416,417] and alterations in feeding behavior [340,473].

Even though it is known that TCDD affects several physiologicalmechanisms involved in the maintenance of body weight balanceand energy homeostasis (previously reviewed e.g. in [338,46,267]),the biochemical factors underlying the wasting syndrome and lead-ing to death are still elusive. Lethally TCDD-exposed animals losetheir body fat stores and even muscle mass. However, rats exposedto high but sublethal doses are able to gain weight (although theirbody weight lags behind that of control rats), increase their feed in-take after fasting, and defend their lowered body weight levelagainst feeding challenges [337,338,416–418]. These factors areconsistent with lowered body weight set-point in dioxin-treated rats[336,337,416–418]. This hypothesis is further supported by findingsfrom an experimental model of simultaneous hyperphagia andunderweight: diabetic rats. Rats rendered diabetic with streptozoto-cin continued to exhibit hyperphagia relative to non-diabetic controlrats after TCDD administration, thus revealing that hypophagia is asecondary rather than the primary effect of TCDD [343].

5.1.4. The role of set-point in body weight regulationEnergy homeostasis, body weight and adiposity are tightly reg-

ulated in animals, albeit the reference point of this homeostasis isbiased to shift upwards to favor excess adiposity resulting in a newbalance that is then defended [289,397,422,511]. This unbalancedregulation – attested in the human population by the current rapidincrease in the prevalence of obesity – may have been evolution-arily beneficial until quite recently [358] thus resulting in a ‘‘thriftygenotype”, or it may represent a genetic drift of the upper inter-vention limit of the body weight after the release of predatorypressure some 2 million years ago [437]. An opposite shift in en-ergy balance towards reduced body fat seems less favored [412]and is seldom observed in a physiological context (except for sea-sonal animals) without external manipulation.

The CNS orchestrates long-term energy balance regulation andimmediate-to-short-term energy repositories (mainly plasma glu-cose and FFA and liver glycogen) on the whole organism level byintegrating the information of the amount of adipose tissue, bloodnutrient levels and environment [76,154,410]. The integratedinformation is further converted into changes in energy intake,expenditure and release from storage [243,411,422]. As early as1969 Hervey proposed that there is a set-point towards whichbody mass (or its correlate) is regulated [173]. Subsequently, thishypothesis has been contested by some researchers contendingthat the body weight would just represent a ‘‘settling point” forall the integrated hormonal, metabolic and behavioral actions thatinfluence energy homeostasis [510]. The critical issue discriminat-ing between the two models is the nature of the response to a

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perturbation: an active defense to oppose the change is indicativeof a set-point [60,208]. Numerous studies in laboratory animalshave demonstrated that body weight is indeed defended [208].Nevertheless, gradual caloric excess can result in a fixed upregula-tion of the defended body weight level, relevant to the obesity con-dition of millions of humans today [249]. In seasonal animalspecies such as the Siberian hamster exhibiting regular rhythmsof body weight that depend on the length of the photoperiods,the point of energy balance is continuously re-adjusted duringthe transition in body weight reflecting an apparent ‘‘sliding set-point” [284] or a dynamic, defended steady state [36]. The compel-ling evidence of the avidity of dioxin-treated rats to defend theirlowered body weight level cited above shows that the wasting syn-drome is accompanied by, and presumably due to, down-shiftedset-point, and thus it can provide a useful model of chemicallyreset ponderostat (a sensor of body weight or its correlate withthe associated physiological machinery to counteract disturbances;analogous to a thermostat) for studies on the regulatory mecha-nisms of energy balance maintenance.

5.1.5. The primary target of energy balance regulation and the wastingsyndrome

For the body weight set-point, the regulated primary variable isstill not established despite the fact that the importance of the sizeof fat deposits in body weight regulation has been known for over50 years [210]. Initially, blood steroids were suggested as the crit-ical correlate of body weight [173]. More recently, this was slightlymodified by hypothesizing that hypothalamic corticotropin-releas-ing factor (CRF) concentration would serve this function [60]. Onthe other hand, studies in seasonal mammals have yielded strongevidence for thyroid hormone availability as a cause for the rhyth-mic alterations in energy balance. Tri-iodothyronin (T3)-releasingimplants placed in the hypothalami of Siberian hamsters were ableto totally block their short-day-induced weight loss [106]. The ulti-mate regulator in this case might conceivably be the thyrotropin-releasing hormone neurons [246]. In the hypothalamus, the regu-lation of thyroid hormone signaling is very complex involving bothglial cell-expressed thyroxin-activating deiodinase D2 and neuro-nal triiodothyronine (T3)-inactivating deiodinase D3 [141]. Finally,synaptic or neuronal plasticity with a perpetual struggle betweenorexigenic and anorexigenic tones [6,92] might form a structuralbasis for a body weight set-point.

According to the CRF hypothesis, a decrease in hypothalamicCRF concentration would stimulate food intake and vice versa. Inrats treated with a dose of TCDD capable of down-regulating bodyweight, plasma ACTH and corticosterone levels are elevated[38,283], which is suggestive of increased hypothalamic CRF. In-deed, a recent study detected increased mRNA levels of CRF inhypothalamic paraventricular (PVN) and ARC nuclei 7 and 14 daysafter TCDD administration, although there was a transient reduc-tion in CRF expression in the central amygdala and bed nucleusof stria terminalis (BNST) at 2 days [283]. PVN has been shown tobe a critical site for the effects of CRF on food intake [228]. Thus,hypothalamic (especially PVN) CRF concentrations are a potentialmediator of dioxins’ impacts on energy balance and worth furtherresearch (see also Section 5.4.3).

As to thyroid hormone balance, plasma thyroxin (T4) levels areseverely diminished after TCDD exposure in TCDD-sensitive rats(substantially more than in pair-fed controls) but elevated in ham-sters which represent a TCDD-resistant species [149,170,335,355].However, this promising correlation is shattered by TCDD-resistantrats which also display significantly decreased T4 concentrations inplasma [335]. The type II deiodinase (deiodinase D2) which con-verts T4 to the biologically more active T3 and is also expressedin the brain (concentrated in a population of specialized glial cells,tanycytes, located in the base and infralateral walls of the third

ventricle) showed a tendency to increased activity in response toTCDD [370,409], plausibly as a compensatory mechanism.

5.1.6. Effect of TCDD on body weight in developing ratsAge and developmental stage of the animal at dioxin exposure

are important factors for dioxin toxicity [424,425]. In adult rats,the sensitivity to the acute lethality of TCDD is reflected in theseverity of the wasting syndrome [338]. Body weight gain is alsoaffected in prenatally dioxin-exposed rats and intimately associ-ated with the general toxicity of dioxin, but at this stage the adultpatterns of sensitivity do not seem to hold. When rat dams of dif-ferently sensitive lines A, B and C (LD50 > 10,000, 830 and 40 lg/kg,respectively) were treated with 1 lg/kg TCDD on gestation day 15,male progeny of all three lines showed lower body weights com-pared with their controls [424]. On the other hand, when male ratsof lines A and B were exposed to a single dose of dioxin betweenpost-natal days 2–56, their growth was immediately retarded withthe effect being more severe with early exposures. The rats dosedyounger did not reach the body weights of their counterparts trea-ted at an older age during the 3-month observation period [425].This finding is in agreement with the hypothesis of altered bodyweight set-point in TCDD-treated rats [336,337,417]. Nevertheless,it still remains to be determined whether the mechanism of inhib-ited body weight gain is the same for adult and developing rats.

5.2. Biochemical signals involved in long-term regulation of energybalance (Fig. 5A)

5.2.1. Signals inducing satietyAnimals and humans adjust the amount of food eaten according

to the caloric content of the food, their energy needs and long-termenergy balance with an inherently robust system to favor a positiveenergy balance. When ample, uniform food is constantly availableand attainable, regular eating patterns integrated with otherbehaviors are established – the major ‘‘zeitgeber” being the light–dark cycle. This also enables the use of distal cues (smell, taste,texture, etc.) in regulating the size of meals and preparatory physio-logical alterations that allow the consumption of larger meals[442,513,515]. Even in nature, with more variation in both availabil-ity and choices of food, the maintenance of energy homeostasis isprimarily based on adjusting the amount of food eaten per meal(meal size), even though this regulation is mixed with or even dom-inated by environmental influences and internal extrahypothalamicnon-homeostatic functions and processes of food reward, satisfac-tion, learning and cognition [289,422].

5.2.1.1. Leptin and insulin. According to the generally accepted ‘‘adi-posity-feedback model” the long-term adjustment of body weightand regulation of energy balance in mammals is based on keepingthe body fat stores constant with the aid of adiposity signals (forrecent reviews, see e.g. [289,397,514]). Two proteins, leptin origi-nating from adipocytes and insulin produced by the pancreas, aresecreted in a direct proportion to the amount of adipose tissueand thus convey information on body adiposity to the CNS by a sat-urable transport system across the blood–brain barrier [24,25].Insulin also has a second, equally important and partly overlap-ping, role in constant regulation of plasma glucose [142,243].

Depletion of leptin or insulin, or their receptors, results in in-creased food intake and obesity mediated by the CNS (it shouldbe noted that type-I diabetes represents a non-physiological stateof low insulin where peripheral glucose utilization is severely im-paired leading to weight loss) [142,397]. Intracerebroventricularadministration of exogenous leptin or insulin induces markedreductions in food intake and body weight [153,163,223,396]. Ifleptin administration continues for about 2 weeks, food intake nor-malizes while body weight does not [163,395,396]. Resistance to

A

B

Fig. 5. A highly simplified, schematic representation of some major centers in the CNS involved in food intake regulation and in the reception of peripheral signals mediatinginformation related to adiposity, nutrients and satiation. (A) Nutrients as well as signals of adiposity and satiation are sensed in multiple nuclei and subregions both withinand outside the hypothalamus with ARC occupying a central position within it. Hindbrain NTS has an essential role in satiety perception and is an autonomous integrator ofthe vagal and hormonal signals. (B) Neuronal pathways involved in satiation-based food intake regulation and non-homeostatic ingestion (food reward) are closely related.LHA is the central convergence point of the dopaminergic reward circuit and the hypothalamic energy balance regulating circuit, and PVN is the major relay site inanorexigenic signaling. GABAergic transmission from the ARC AgRP/NPY orexigenic neurons to PBN is important for non-homeostatic anorexia. The CNS nuclei and areas aredesignated anorexigenic (red), orexigenic (green) or integrating by their primary role based on e.g. lesion experiments. Directly or indirectly excitatory connections aredepicted by bright green links and directly or indirectly inhibitory connections by bright red links. PVN paraventricular nucleus, DMH dorsomedial hypothalamus, VMHventromedial hypothalamic nucleus, LHA lateral hypothalamic area, VTA ventral tegmental area, ARC arcuate nucleus, NTS nucleus tractus solitarii, PBN parabrachial nucleus,Nac nucleus accumbens. Modified from [289,397].

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leptin and insulin occurs in obesity and type-II diabetes[118,163,287] as well as in inflammation in the CNS [352,451].

5.2.1.2. Impacts of TCDD on insulin and leptin. At doses high enoughto cause body weight loss, TCDD reduces circulating insulin levelsin rats [148,149]. At lethal doses, the change is similar to thatoccurring in pair-fed control rats and therefore seems to largelyrepresent a secondary effect [148]. At a sublethal dose, however,diminished feed intake apparently cannot account for the decrease

in plasma insulin [148]; indeed, a significant impairment of glu-cose-stimulated insulin secretion was reported in islets isolatedfrom TCDD-treated rats [310]. On the other hand, the function ofinsulin may be enhanced by TCDD. A recent study in 12-h fastedmice challenged with glucose revealed that already 24 h after a rel-atively low dose (10 lg/kg) of TCDD, plasma insulin levels in-creased less than in control animals, although plasma glucoseconcentrations behaved in the same way in both groups [238]. Inrats made diabetic with streptozotocin and a high-fat diet, TCDD

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ameliorated the induced hyperglycemia [125]. Likewise, in theonly study applying the ‘‘golden standard” method for the analysisof insulin sensitivity, euglycemic insulin clamp [270], glucose dis-posal rate was found to be increased by TCDD in rats, indicatingaugmented insulin sensitivity [308] (published in Japanese). Thesefindings thus imply that TCDD improves insulin sensitivity at thewhole organism level, at least in rats and mice. Unfortunately,there are no data available regarding the transport of insulin fromblood to the CNS in TCDD-exposed animals. Should that also be en-hanced, insulin could well be involved in the molecular pathogen-esis of the wasting syndrome despite the decrease in its circulatinglevels.

As to the possible influence of dioxin on leptin, there is a paucityof data in the literature. Unchanged plasma leptin levels were re-ported 24 h after a low dose of TCDD not expected to influencebody weight in rats (1 lg/kg) [310]. In a small-scale experimentat higher doses, we noted that plasma leptin concentration was ini-tially elevated on day 1 after TCDD exposure but then, three to se-ven days later, took an identical downhill course in both TCDD-treated L-E rats and their pair-fed controls [465]. However, in thosedays a rat-specific leptin antibody was not yet available and wehad to resort to an antibody raised for mouse leptin. Further stud-ies are clearly warranted to verify and extend these preliminaryfindings.

5.2.2. Signals inducing initiation of feeding5.2.2.1. Ghrelin. The best-characterized peripheral signal related tofood intake initiation is ghrelin, either considered to be a true hungersignal [364,516] or emphasizing its role as a feeding stimulatory sig-nal and a longer-term augmenting factor of feeding [37,92,191].Peripherally, ghrelin is mainly produced by endocrine X/A-like cellsin the gastric mucosa [83,221], and centrally by specialized nervecells in ARC. It is a highly potent stimulator of food intake in humansand experimental animals when given either peripherally or into theCNS, and its plasma levels rise before meals and fall shortly aftereating [37,364,516]. The relationship of the plasma ghrelin to foodintake stimulation may be direct [37,92,364] or conveyed via thevagus nerve with a possible involvement of de novo hypothalamicproduction of ghrelin [194].

5.2.2.2. Nutrient levels and feeding initiation. Neurons in the hypo-thalamus, elsewhere in the CNS and peripherally are capable ofsensing the levels of glucose, fatty acids and amino acids (leucine),although glucose through astrocyte-produced lactate is their al-most exclusive source of energy except for in a prolonged fast[243,397,453]. In addition, the CNS receives information of (atleast) peripheral glucose level through vagus, ghrelin and insulin.This information is primarily processed in the hypothalamus[243,397,453].

Direct nutrient sensing of foremost glucose is important inmaintaining the short-term energy stores at physiological levels,but it is also intricately intertwined with the long-term energy bal-ance regulation. A decrease in blood glucose below the euglygemiclevel triggers an immediate peripheral response starting with thesecretion of glucagon and elicitation of feeding, and this responsecan be prevented or induced by hypothalamic glucose administra-tion or depletion, respectively [243,453]. These temporary or long-er-lasting downward and upward alterations in plasma glucoselevels are sensed by glucose-inhibited and -excited neurons inthe hypothalamus and elsewhere in the CNS, and also relayed tothe CNS by at least insulin, ghrelin and vagal afferents [243,435,453,521]. These signals cause activity changes in the glucose-responsive neurons. The induced changes are most likely basedon KATP channels and type II glucose transporters (GLUT2), coupledintracellularly with mitochondrial uncoupling-protein 2 (UCP2),glucokinase and AMP-activated protein kinase (AMPK) [397,453].

The glucostatic/glucoprivic feeding initiation (possibly involvingghrelin [435]) is assumed to come into play in environmentally-induced non-physiological, acute energy depletion states [102]. Itis initiated by glucoreceptors in the brainstem (hindbrain), but itis mediated by several other brain regions including hypothalamicnuclei [383]. Although a slight drop in plasma glucose precedes thespontaneous initiation of feeding in rats and humans [61], it is con-sidered to be a feeding initiation-related phenomenon but not aprimary initiation signal per se.

5.2.2.3. Interference of TCDD with feeding initiation. No studies havehitherto addressed the possible role of ghrelin in the wasting syn-drome. On the other hand, glucoprivic challenges, brought abouteither with the competitive inhibitor of glycolysis at the glucose-6-phosphate isomerase step, 2-deoxy-D-glucose (2DG) [504], orwith a non-physiologically high acute dose of insulin, have beenimposed on TCDD-treated rats. A high but sublethal dose of TCDD(1000 lg/kg), which entirely prevented further growth of TCDD-resistant H/W rats, rapidly abolished the feeding response to gluco-privation whether induced by 2DG or insulin [340]. This changealso proved to be persistent as it was still complete for 2DG andpartial for insulin at 2 months after exposure [337]. The inabilityof TCDD-exposed rats to respond by eating to an acute energeticcrisis may be the key reason for their reported sensitivity to insulinlethality [149,337,340].

In C57BL/6 mice, TCDD at a dose (116 lg/kg) that did not affectthe overall body weight gain of the animals caused a swift (within24 h) and long-lasting (30 days) reduction (20–30%) in glucosetransport in the brain. GLUT1 protein expression was similarlydampened (GLUT2 was not analyzed) [260]. A total subdiaphrag-matic vagotomy failed to appreciably modify the effect of TCDDon feed intake or body weight in L-E or H/W rats [463], arguingagainst a decisive role for vagal signals in the wasting syndrome.It is of interest, however, that vagotomy had an additive diminish-ing impact on body weight which resembled that of a dorsomedialhypothalamus (DMH) lesion (see Section 5.4.1.3). The fact thatvagotomy results in body weight loss has been known for a longtime; exactly why this happens is still obscure [415].

5.3. Short-term (meal-to-meal) regulation of feeding: peripheralpeptides

When feeding has commenced, a number of messengers emergeto suppress appetite in response to food ingestion and act as sati-ation signals. These satiation signals are small peptides producedin the intestine (e.g. cholecystokinin [CCK], glucagon-like peptide1 [GLP-1], oxyntomodulin, peptide-YY [PYY], enterostatin) or inthe pancreas (amylin and pancreatic polypeptide). Most of themact primarily or partially via vagal afferent fibers [33,54,68,99,200,222,387]. Experimentally, they are defined as substances thatresult in a reduction of the meal size when given at the start offeeding. They also work at physiological concentrations and with-out generating malaise or incapacitation [514]. Traditionally, thesatiation signals were considered to be short-acting and only rele-vant to a single meal, but at least some of them are currentlythought to have a role in longer-term energy balance regulationas well [37,516]. In contrast to the long-term satiety signals insulinand leptin, at least PYY and GLP-1 are able to cross the blood–brainbarrier via non-saturable mechanisms [519].

5.3.1. Contribution of the short-term signals to TCDD-induced wastingFrom some 2 weeks on after exposure to 1000 lg/kg TCDD, H/W

rats started to exhibit a feeding behavioral change which wasinterpreted as augmented sensitivity to post-ingestive satiety (orsatiation) signals. It manifested as reduced consumption of glucoseor sucrose solution but increased consumption of the energetically

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valueless saccharine solution, and diminished feeding in pre-load-ing experiments if the pre-loads yielded energy [336,341]. Thesealterations persisted for at least several months. However, con-comitantly the feeding response to peripherally administeredCCK remained unaffected [337,341]. As noted earlier, vagotomyfailed to modulate the effects of TCDD on feed intake or bodyweight in either L-E or H/W rats; thus it is unlikely that these ef-fects were mediated by vagal afferents. Likewise, portocaval anas-tomosis did not appreciably interfere with the effect of TCDD ondaily feed consumption or body weight gain in these rat strains[463].

5.4. Regulatory centers and neurotransmitters in the CNS involved inenergy balance (Fig. 5B)

5.4.1. Hypothalamic nuclei and neuropeptides5.4.1.1. ARC at the crossroads of insulin and leptin signaling. Energyhomeostasis and body weight are now thought to be regulatedby neuronal circuits, which signal using specific neuropeptides,rather than by specific hypothalamic nuclei. However, the ARC, inparticular, is thought to play a pivotal role in the integration of reg-ulatory signals. As described earlier (Section 5.2.1.1), informationon the amount of adipose tissue, reflecting the long-term energystatus, is mainly signaled to the CNS by leptin and insulin [118].Although they both have receptors at multiple sites in the CNS,those concerned with energy balance reside for the most part inthe hypothalamus, particularly in ARC, ventromedial hypothala-mus (VMH) and DMH, as well as in the lateral hypothalamic area(LHA) and PVN [223,243,301].

In ARC, the effects of insulin and leptin are closely integrated,even intracellularly at the level of phosphoinositide 3-kinase, tomodulate two populations of neurons acting as the cardinal regula-tors of energy balance [118,243,397]: the orexigenic agouti-relatedpeptide/neuropeptide Y (AgRP/NPY) neurons reduce their activityand neurotransmitter expression by leptin and insulin stimulation,whereas the anorexigenic pro-opiomelanocortin/cocaine- andamphetamine-regulated transcript (POMC/CART)-expressing neu-rons function in the opposite way. However, the effects of insulinand leptin are not fully identical. While leptin depolarizes POMC/CART neurons to increase their firing rate and hyperpolarizesAgRP/NPY neurons to inhibit their electrical activity, insulin hyper-polarizes and silences both these two types of neurons by mecha-nisms not totally resolved [175,289,397].

Both AgRP/NPY and POMC/CART neurons express the inhibitoryneurotransmitter gamma-amino butyric acid (GABA), and POMC/CART neurons appear to be under constant suppression by theirneighboring AgRP/NPY-neurons through the release of GABA[132,276]. ARC also receives and projects various inhibitory andexcitatory contacts to other areas in the hypothalamus, and thesesynapses as well as the synapses amongst neurons in ARC arefound to be morphologically modulated by ghrelin and leptinadministration or fasting [6,289,397]. This synaptic or neuronalplasticity (based at least partly on the continuous activity of AgRPneurons) is proposed to be an important mechanism in hypotha-lamic energy balance regulation controlled by leptin/ghrelin bal-ance and explaining the long-term effects of ghrelin on foodintake [6,92].

In addition to leptin, insulin and ghrelin, plasma nutrient levelsinfluence the activity of orexigenic and anorexigenic neurons inARC. Glucose inhibits AgRP/NPY neurons and activates POMC/CARTneurons, while intracerebroventricularly infused oleic acid (a long-chain fatty acid) reduces NPY expression in the hypothalamus, anda protein-rich meal activates POMC/CART neurons [244,353,397].

5.4.1.2. Hypothalamic centers and networks outside the ARC. Beyondthe ARC, AgRP/NPY and POMC/CART neurons continue to have clo-

sely intertwined connections. Both of them innervate PVN, LHA,VMH and DMH as well as several other hypothalamic and extra-hypothalamic nuclei, notably the parabrachial nucleus (PBN)[6,51]; POMC/CART neurons extend their connections in the brain-stem also to the nucleus tractus solitarii (NTS) [430]. Of the inner-vated nuclei and areas, the VMH, PVN, LHA and DMH have beenassigned special roles in hypothalamic food intake regulation andexternal connections. Based on lesion studies, the VMH has tradi-tionally been referred to as the satiety center, and it is still todayassumed to have an independent role in food intake promotion,responding to at least glucose and leptin [300,397]. The anorexi-genic PVN and the orexigenic LHA are important relay sites ofinformation for autonomic and neuroendocrine effects and for foodintake with afferent connections to the brainstem. LHA has alsoconnections to cortical neurons and is an integrating nucleus ofthe energy balance and reward circuits [118,289,300]. The food in-take-promoting DMH is innervated by NPY/AgRP-positive fibersfrom ARC and responds directly to at least glucose and leptin. Ithas an important autonomous role in food intake and body weightregulation [32,218,532].

The strongly orexigenic NPY signals through Y1, Y2 and Y5receptors, and LHA seems to be the principal site of its action eventhough it also inhibits neuronal firing in PVN and VMH [6,69]. Theorexigenic effect through LHA is generally believed to be mediatedby melanin concentrating hormone (MCH), with a shorter-terminfluence by orexin/hypocretin. However, the mechanism by whichthe MCH secretion is stimulated is unknown [51,155], albeit recentfindings point to a marked effect of LHA GABAA receptors in feed-ing regulation [474]. The anorexigenic melanocortin system isbased on melanocyte-stimulating hormone (a-MSH), producedfrom POMC in POMC/CART neurons and secreted together withCART [6,92]. The principal second order nucleus in melanocortinsignaling is PVN, which contains high levels of melanocortin recep-tors 3 and 4 (MC3R, MC4R) stimulated by a-MSH [6]. It is also animportant convergence point of anorexigenic and orexigenic sig-naling, since AgRP, the second product of AgRP/NPY neurons, isan antagonist of melanonocortin receptors, and (as described ear-lier) CRF exerts its anorexic effect in the PVN.

5.4.1.3. Influence of hypothalamic lesions on the wasting syn-drome. The hypothalamus has been known for decades to be akey brain region in the regulation of feeding and energy balancewith the earliest publications dating back to the early 1950s [17].Lesions of hypothalamic nuclei are rather massive and indiscrimi-nate manipulations of brain regulatory sites as it has turned outthat the notion of distinct ‘hunger or satiety centers’ is far too sim-plistic, as outlined in the previous sections. Nevertheless, it is well-established that site-specific lesions of critical areas in this net-work (such as VMH or DMH) can markedly alter the defended bodyweight [249].

A lesion of the VMH induces metabolic obesity which resultsnot only from hyperphagia but also from disturbances in the auto-nomic nervous system [128,215]. The lesion usually involves ARCin addition to the actual ventromedial nucleus [249]. It was of greatinterest to see whether the metabolically counteracting impact ofVMH lesion could overcome the catabolic dyscrasia elicited byTCDD. It turned out that when VMH lesion preceded TCDD treat-ment, it surprisingly aggravated TCDD-induced wasting syndromein both TCDD-sensitive L-E and TCDD-resistant H/W rats [467]. Theexacerbation was greater if the rats had reached obesity beforeTCDD exposure (i.e. if exposed 2 weeks versus 4 days after theoperation). The doses of TCDD used in that experiment wereclearly sublethal to sham-operated rats and the response to VMHlesion without TCDD was hyperphagia and obesity. Interestingly,a single lesioned L-E rat responded to TCDD disparately by gainingweight at a tremendous pace and weighing 60% more at 6 weeks

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than the obese lesioned control rats. In the case when the rats werelesioned 6 weeks after TCDD exposure, at a time when body weighthad stabilized to a lower level, no aggravation was seen any longer(the lesioned TCDD-exposed rats grew slightly faster than thesham-operated TCDD-exposed partners). These findings suggestprotective involvement of regulatory networks either traversingthe VMH (including ARC) or operating in it at the initiation phaseof the wasting syndrome.

Subsequently, the possible interference of DMH and PVN lesionswith TCDD toxicity was also investigated in our laboratory on H/Wrats treated with a high but non-lethal dose of TCDD (1000 lg/kg).To maximize the effect of PVN lesion on body weight, the rats inthat experiment were on a highly palatable diet. Both lesions gen-erated the expected outcome in vehicle-treated rats (retarded orenhanced body weight gain for DMH and PVN lesions, respec-tively). There was no interaction between the effects of DMH lesionand TCDD, they were purely additive. In the case of PVN, in con-trast, the lesioned rats that initially were overweight diminishedtheir feed consumption more than the sham-operated counter-parts, with the result that 7 weeks after TCDD exposure the bodyweights of the two groups were indistinguishable [469,470]. Thus,neither of these two regulatory centers in the hypothalamus ap-pears to be directly involved in TCDD’s actions on feed intakeand body weight. The studies with TCDD further suggest that a le-sion of the DMH, but not that of the PVN, is able to reset the pon-derostat because the ultimate body weight level pursued by TCDD-treated rats was only affected by the former manipulation. Itshould be borne in mind that these experiments were carried outin TCDD-resistant H/W rats which do not exhibit the fatal formof the wasting syndrome.

5.4.1.4. Effects of TCDD on hypothalamic neuropeptides. At 6 daysafter a sublethal TCDD dose (15 lg/kg) to Sprague–Dawley rats,an increased expression of NPY, POMC and CART mRNA was de-tected in ARC, and in LHA also MCH expression was increased[117]. In keeping with these findings, a dose (50 lg/kg) close tothe LD50 value of the same strain of rat increased POMC mRNA lev-els in ARC at 7 and 14 days; at the latter time-point, a significantelevation was also found at 12.5 and 25 lg/kg doses [283]. In atime-course study spanning 6–96 h after TCDD exposure (50 lg/kg), a tendency to lowered levels in mRNA expression of orexigenicfactors was initially seen in hypothalamic blocks of TCDD-sensitiveL-E rats. By 96 h, this had converted to an increased expression ofNPY and AgRP, probably as a secondary change to TCDD-inducedhypophagia. Similar general patterns, although delayed, occurredin TCDD-resistant H/W rats [258]. Thus, there is limited evidenceof direct interference of TCDD with the regulatory neuropeptides.More information is needed especially on the early stages of dioxinintoxication.

5.4.2. Amine neurotransmittersThe classical monoamine neurotransmitters serotonin (5-

hydroxytryptamine, 5-HT), dopamine and noradrenaline as wellas the biogenic amine histamine act in conjunction with neuropep-tides and peripheral hormones to control energy balance. Seroto-nin has overall a suppressive effect on food intake and bodyweight e.g. in PVN, VMH and DMH acting mainly through 5-HT1B

and possibly 5-HT1C receptors [372]. The autoreceptor 5-HT1A hasthe opposite impact on feeding mediating hyperphagia [81]. Ithas recently even been proposed that leptin may exert its actionon food intake by inhibiting the production of serotonin in brain-stem neurons. This would then curtail appetite through reducedactivity of 5-HT1A in ARC leading to increased POMC expressionand decreased NPY and AgRP expression [520]. Serotonin is syn-thesized from tryptophan whose brain concentrations are rate-lim-iting for the synthesis [64].

Dopamine appears to be more influenced by food intake ratherthan influencing it [372]. However, mice which lack dopamine, dueto the absence of the tyrosine hydroxylase gene, have fatal hypo-phagia [519]. Noradrenaline may have dual effects on food intake:in PVN activation of a2 receptors stimulates feeding whereas a1

agonists suppress it [372]. Histamine is mainly involved in circa-dian feeding rhythms mediating or accentuating the effects of lep-tin via H1 receptors [193,524].

GABA is the main inhibitory neurotransmitter in the CNS. Re-cent findings underline the importance of GABAergic transmissionof the AgRP/NPY-neurons in maintaining feeding [517,518]. Loss ofGABAergic transmission of these cells to PBN leads to activation ofpostsynaptic neurons and starvation, and this has been proposed tobe related to the activation of circuits that normally promote nau-sea-induced anorexia. As described above, GABA is orexigenic byway of its inhibitory action on POMC/CART cells in the ARC whereboth GABAA and GABAB receptors have been demonstrated. Most ofthe AgRP/NPY neurons also contain the GABA synthesizing en-zyme, glutamic acid decarboxylase [276]. Glutamate, in turn, isthe dominant excitatory transmitter in hypothalamic neuroendo-crine regulation. When injected into the LHA, it elicits an intensefeeding response in satiated rats via activation of MCH and orexinneurons [276].

5.4.2.1. Effects of TCDD on amine neurotransmitters in the CNS. At 4and 10 days after a single dose of 50 lg/kg, TCDD was found to in-crease serotonin turnover uniformly across all macrodissectedbrain areas, including the hypothalamus, in L-E but not H/W rats[477]. The effect was specific to serotonin as there were no majorchanges in brain concentrations or turnover rates of noradrenalineand dopamine in either strain. This general pattern has been veri-fied in other rat strains (reviewed in [338]). The enhanced turnoveris due to increased plasma levels of free tryptophan which are re-flected in brain tryptophan concentrations [480]. Although it hasproven to be a reliable indicator of acutely toxic exposure to TCDDand other dioxins in rats [479], accelerated brain serotonin turn-over does not appear to be causally related to the wasting syn-drome, because depletion of brain serotonin by the selectiveneurotoxic analog, 5,7-dihydroxytryptamine, did not influence it[439]. In agreement with this, plasma and brain tryptophan werenot altered in TCDD-exposed guinea pigs in the face of markedbody weight loss while both were increased in TCDD-treated ham-sters with little effect on body weight [481].

A slight increase was recorded in histamine concentrations inthe whole hypothalamus at 28 h [464] and in the median eminenceat 25 h after TCDD treatment [471]. They might bear on the alteredcircadian feeding rhythms observed in TCDD-exposed rats (seeSection 5.7).

Fully supporting the reasoning above on the role of monoam-ines in TCDD toxicity, intervention with haloperidol or amperozide(dopamine antagonists), phenoxybenzamine (a-adrenoceptorblocking agent) or p-chlorophenylalanine (serotonin synthesisinhibitor) failed to modulate TCDD-induced wasting syndrome inL-E rats [339].

There is evidence from prenatally exposed animals that dioxinsmay affect GABAergic and glutamatergic neurotransmission in theCNS. For example, in rats the mRNA expression of glutamate recep-tor subunits NR2B (NMDA) and GluR1 (AMPA) was reduced whilethat of NR2A (NMDA) was enhanced in cortex and in the hippo-campus postnatally after prenatal TCDD exposure (0.1–0.8 lg/kg,GD15) [178,196]. TCDD administration on GD11.5 at a dose of5 lg/kg to the mouse dam was found to compromise the differen-tiation of GABAergic neurons in ventral telencephalon, whichmight offer an explanation for the experimentally observed, usu-ally subtle, learning alterations (either retardation or facilitation)in gestationally TCDD-exposed rats and monkeys [145,404,506].

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Furthermore, TCDD was postulated to induce the reported alteredmale sexual behavior and female-type LH-surge [197], ‘‘demascul-inization”, by interfering with the estradiol-dependent apoptosis ofGABA/glutamate neurons of the anteroventral periventricular nu-cleus in the preoptic area [166,327]. In vitro studies with neuronalcells have also revealed that TCDD may increase cellular calciumconcentration and activate protein kinase-C through NMDA recep-tors [213,254], and up-regulate NMDA receptor subunits (NR1,NR2A and NR2B) [74]. However, next to nothing is known aboutthe possible modulation of GABAergic or glutamatergic neuro-transmission by dioxins in the context of energy balance in adultanimals.

5.4.3. Nitric oxideIn recent years, the importance of nitric oxide in the regulation

of energy balance has emerged. The orexigenic peptides ghrelin,NPY and orexin-A all exert their effects on food intake, at least inpart, through nitric oxide which is synthesized by neuronal nitricoxide synthase (nNOS) [112,139,285]. Conversely, leptin inhibitsnNOS and thereby reduces nitric oxide levels [285]. Another iso-form, inducible NOS (iNOS), has been suggested to play an antago-nistic role to that of nNOS by mediating anorexia [286] and may beinvolved in cancer cachexia [494].

5.4.3.1. Involvement of nitric oxide in TCDD toxicity. Administrationof the irreversible selective inhibitor of nNOS, N-nitro-L-arginineto TCDD-treated animals either with slow-release osmotic mini-pumps or by repeated injections caused an interesting divergencein responses between mice and rats. In mice, the interventionattenuated the acute toxicity of TCDD, whereas in rats it exacer-bated it. However, in feed intake a departure from placebo-admin-istered, TCDD-treated rats was only seen during the first 5 days(feed intake was not measured in mice) [487]. In another study,a decrease in whole brain nNOS protein was first detected by Wes-tern blot in Long-Evans rats at one and 2 weeks post-exposure to50 lg/kg TCDD. Next, NAPDH-diaphorase staining was used toselectively analyze nNOS levels by immunohistochemistry inhypothalamic nuclei of identically treated rats of the same strain.Diminished staining was recorded in PVN, LHA and perifornical nu-cleus at 2 weeks after TCDD with a downward tendency at 1 week[72]. Thus, further studies are warranted on both iNOS and nNOS inTCDD-treated rats and mice.

5.4.4. Caudal brainstem in energy balance regulationThe caudal brainstem (‘‘hindbrain”), the NTS in particular, is the

main site to receive information from peripheral energy metabo-lism, chiefly by way of the vagal afferent fibers. The caudal brain-stem is involved in the control of meal size by signals arisingfrom the mouth and gastrointestinal tract based upon the chemicaland mechanical properties of food which are conveyed to the NTS,an important integrator in energy balance regulation [37,132,152].Caudal brainstem circuits are sufficient for meal size control, initi-ate glucoprivic feeding, contain systems for satiating signal (CCKand GLP-1) and leptin interaction, and have multiple afferent con-nections to the hypothalamus [152,383].

The caudal brainstem has not been addressed in the context ofthe impacts of TCDD on energy homeostasis. However, the promi-nent effects of TCDD on glucoprivic feeding (Section 5.2.2.3) andmeal size (Section 5.7) would definitely justify more attention tobe paid on this brain region in the future.

5.5. Satiation versus reward in the regulation of energy balance

The central system integrating information on the amount ofadipose tissue, blood nutrient levels and environment resides inhypothalamic and hindbrain nuclei, amongst a myriad of connec-

tions with other brain areas involved in motivation, reward andcognition. While this organization is generally accepted and thor-oughly described, the primacy of the central integration as opposedto a more decentralized regulation is debated [118,289,422].

In satiation-based food intake regulation, the energy balance setsthe general sensitivity of the hypothalamus – hindbrain system tosatiety signals affecting the meal size. An abundance of stored andcirculating nutrients enhances sensitivity to the meal terminatingsignals [289,300,514]. On the other hand, the incentive (reward)value of palatable food can override satiety signals and promoteexcess food ingestion. Aptly, this regulation of food intake is alsocalled non-homeostatic. The major components of reward are want-ing, liking and learning [35], with partly overlapping and only par-tially known CNS circuits and signals [118,223,300,422].

The reward circuitry is complex and involves interactions be-tween several signaling systems. The reward-based regulation ofeating is intimately linked to the midbrain mesolimbic dopaminer-gic (DA) system which contains a set of ventral tegmental area(VTA) neurons that innervate the striatum, amygdala and prefron-tal cortex [300,422]. Leptin and insulin act directly on VTA DA neu-rons reducing dopamine release and diminishing food seeking andintake [118], whereas food restriction and ghrelin induce an oppo-site effect [223,422]. Notably, a chronic absence of leptin impairsthe mesolimbic DA system [300]. LHA orexin neurons project toVTA and the stimulation of LHA promotes strongly food (and otherreward, e.g. drug) seeking, and this type of behavior is suppressedby leptin [118,300,422]. Subconscious ‘‘liking-reaction” to food canbe elicited by hindbrain neural circuits and seems to be related tothe cannabinoid and l-opioid systems with the involvement of thestriatal nucleus accumbens (NAc) and ventral pallidum [422]. NAchas also been shown to inhibit MCH neurons in LHA, which sendinhibitory efferents back to NAc, conceivably enabling continuousactivation of MCH-containing neurons [399]. Leptin and ghrelinhave both been shown to augment memory and learning, whilethey have opposite effects on food intake [422]. Opioids play animportant role in the reward circuitry, as a lack of either encepha-lin or b-endorphin in mice abolishes the reinforcing property offood, regardless of the palatability of the food tested [519].

5.5.1. Effects of TCDD on the reward circuitryOriginally, increased c-Fos expression (a widely-used index of

neuronal activation) was detected in several hypothalamic nuclei,central amygdala and BNST 3–4 days after TCDD (50 lg/kg) admin-istration to rats [71]. Later on (using an identical exposure setting),the same group reported an increase of methionine–encephalinimmunoreactivity in various forebrain nuclei, e.g. central amyg-dala, PVN, medial preoptic nucleus and BNST 2 weeks after TCDDtreatment [70]. This could be a compensatory reaction to the bodyweight loss and hypophagia provoked by TCDD. The opioid antag-onist naloxone decreased 24-h fast-induced feeding in control rats.In H/W rats treated with a high dose of TCDD (1000 lg/kg) 3months earlier, this suppression was blunted (the circadian feedingrhythm of the TCDD-treated rats was shifted (see Section 5.7), andthus they ate more than their corn oil-treated partners during the6-h observation period at daytime whether given saline or nalox-one) [337]. Hence, there is little evidence of a critical role for thereward circuitry in the TCDD-induced wasting syndrome, but theavailable data are also scant.

5.6. Enhanced neophobia in TCDD-treated animals

TCDD appears to affect feeding behavior in a specific manner.Certain alterations in feeding behavior emerge as early as a fewhours after TCDD exposure [473]. The selective nature of these im-pacts is revealed by the fact that other than behavioral effects onfeeding, few behavioral alterations are observed in TCDD-exposed

J. Lindén et al. / Frontiers in Neuroendocrinology 31 (2010) 452–478 467

adult animals [429]. Reported disturbances in the behavior do ex-ist, but they originate from prenatal and/or lactational exposure todioxins [16,45,420,506].

Exposure of adult rats to TCDD not only reduces total feed con-sumption but also results in a conspicuous and peculiar alterationin food preferences in certain contexts. Usually rodents like sweetand fatty tastes and therefore prefer cheese and chocolate to regu-lar chow, but if these new items are first introduced to the rats atTCDD exposure or soon afterwards, TCDD-treated rats display astriking avoidance of them. This change emerges rapidly, in a fewhours after exposure. Furthermore, the neophobia is not sex- orstrain-specific and bears no apparent correlation with sensitivityto the acute toxicity of TCDD. The deviant behavior, avoidance ofa tasty food item (chocolate), was observable at sublethal dosesand it persisted for at least 5 weeks [473].

Recently, we have further pursued these behavioral studies andour preliminary data show that the phenomenon is not confined torats but also occurs in TCDD-treated mice. In them, functional AHRseems to be needed for the neophobia (S. Lensu, R. Pohjanvirta, J.Tuomisto and J.T. Tuomisto, unpublished results). Moreover, theavoidance of novel food items is detectable at doses which are solow that they have no effect on body weight or total energy intakein rats. Therefore, this accentuated neophobia-like syndrome ap-pears to be an extremely sensitive toxic endpoint which emergesat a notably early phase of TCDD intoxication and warrants furtherstudies.

Gustatory or food neophobia means an innate fear of new foods,and it exists in humans and animals [97,119]. The abstaining ofingestion of large amounts of a new, potentially toxic food maybe genetically determined and beneficial for survival [184]. Gusta-tory neophobia is mediated by insular cortex [386] and basolateralamygdala (BLA) [376], and glutamate NMDA receptors participatein its mediation [119]. Conditioned taste aversion, an efficientlearned aversion of a novel taste associated with transient visceralillness, is mediated by the same CNS areas, principally BLA. As de-

Table 1Experimental evidence that TCDD may affect the central regulation of energy balance.

Factor/systema

Comments

CRF CRF, TRF and synaptic plasticity have been implicated as primary tashown to alter CRF mRNA expression in the CNS

Insulin TCDD reduces directly or indirectly plasma insulin and impairs islet cinsulin sensitivity. For insulin lethality, see ‘‘blood glucose”.

Leptin Small doses of TCDD did not induce changes in leptin levels but alt

Blood glucose Central and peripheral glucose depletion induces feeding. This respoby TCDD, possibly explaining sensitivity to insulin lethality

Satiatingsignals

After a relatively high dose (1000 lg/kg) of TCDD H/W rats exhibiteenhanced response to post-ingestive satiation signals. However, thewas not altered

VMH VMH lesion (inducing metabolic obesity) aggravated the wasting sybefore TCDD administration, but did not have a marked effect after

DMH DMH lesion (inducing hypophagia and suppressing 2DG-elicited feedweight in H/W rats

Neuropeptides In SD rats, a sublethal dose of TCDD increased NPY, CART, POMC andComparable doses increased POMC expression in ARC at 14 days, wPOMC expression in ARC both at 7 and 14 days. In a study on L-E rainduced an initial lowering tendency in the mRNAs of hypothalamiincreased expression of NPY and AgRP

Neophobia Avoidance of a novel tasty food item was observed in TCDD-treatedleast 5 weeks. Recent unpublished findings extend this phenomenonavoidance of novel food items seems to be an exceptionally sensitiv

Feedingrhythm

TCDD treatment has been shown to alter the normal circadian pattefindings point to strain- and dose-dependent dynamic chains of alte

a See also Fig. 5 A and B.

scribed earlier (Section 5.4.2.1), there is mounting evidence thatTCDD can interfere with the glutamate receptors by prenatal expo-sure. The augmented neophobia-like behavior of TCDD-treated ani-mals reinforces the need for information on whether this alsooccurs in the case of adult exposure.

5.7. Disrupted circadian feeding rhythm in TCDD-exposed rats

TCDD treatment has been shown to alter the normal circadianpattern of feeding in rats. About 2 weeks after exposure to a highbut sublethal dose of TCDD (1000 lg/kg), TCDD-resistant H/W ratsstarted to exhibit an increase in their proportional feed intake duringthe light hours of the day. This shift persisted for over 4 months[336,337]. Similar findings have been reported in TCDD-sensitiveL-E [339] and Sprague–Dawley rats [75]. To further investigate thisand other possible aberrations in consummatory behaviors, we haverecently set up an automated system enabling continuous monitor-ing of feed and water intake to analyze feeding and drinkingmicrostructures in both L-E and H/W rats. We have found strain-and dose-dependent dynamic chains of alterations to emerge soonafter exposure. The preliminary data have revealed that in L-E ratsat both supralethal (100 lg/kg) and sublethal (10 lg/kg) doses ofTCDD, the decrease in the total amount of feed eaten results from areduced size of meals with the reduction being larger at night thanat daytime. In contrast, in H/W rats the decrease was due to a low-ered number of meals throughout the day. We further observed thatof the two circadian peaks in the feeding, which in control rats takeplace shortly after lights off in the evening and just before lights on inthe morning, the morning peak diminished in TCDD-treated L-E rats(S. Lensu, J. Lindén, P. Tiittanen, J. Tuomisto and R. Pohjanvirta,unpublished data).

The reason(s) for these readjustments in feeding rhythms arestill obscure. Several biological phenomena including feedinghave circadian rhythms controlled by clock genes which belongto the bHLH/PAS protein superfamily [211]. Expression of the

References

rgets of energy balance regulation. TCDD was [6,60,92,106,246,283]

ell insulin secretion, but increases whole-body [125,148,149,238,270,308,310]

erations were reported at higher doses [310,465]

nse (elicited by 2DG or insulin) was abolished [149,337,340]

d feeding behavioral changes interpreted as anir response to peripherally administered CCK

[336,337,341]

ndrome in both L-E and H/W rats if performedTCDD-induced body weight reduction

[467]

ing) had an additive effect with TCDD on body [32,470]

MCH mRNA expression in ARC or LHA at 6 days.hile a dose close to the LD50 value increasedts focusing on days 1–4, a lethal dose of TCDD-c orexigenic factors. This was followed by an

[117,258,283]

rats at sublethal doses and it persisted for atto mice and attest to its AHR-dependency. Thee response to TCDD in rats

[473] Unpublished: seeSection 5.6

rn of feeding in rats. Recent unpublishedrations soon after TCDD exposure

[75,336,337] Unpublished: seeSection 5.7

468 J. Lindén et al. / Frontiers in Neuroendocrinology 31 (2010) 452–478

AHR protein fluctuates in several tissues of mice and rats in thecourse of the day [293,378]. Although the physiological role ofthe AHR in circadian rhythms is still debatable, activation of itby TCDD leads to disturbances in the circadian time-keeping sys-tem. Recent findings support a role for the clock genes Sim1,Per1 and Per2 in the modulation of AHR-mediated responses toTCDD in different organs in vivo [293,367,368] and in vitro[133,522]. However, in a study by Korkalainen et al. [224], nosignificant effects of TCDD were found on the hypothalamicmRNA levels of Sim1 or Per2 in L-E or H/W rats.

Table 1 summarizes the available evidence of the interference ofTCDD with the central regulation of energy balance.

6. Conclusions and future prospects

Despite extensive and numerous studies over the last three dec-ades, the ultimate reason for the extremely high acute toxicity ofcertain dioxins, foremost TCDD, has remained enigmatic. The acutetoxicity of TCDD is intimately coupled with the wasting syndrome,which in itself poses an interesting challenge to science. TCDDseems to target the regulatory mechanisms of body weight andfood intake in a highly specific manner as evidenced by the abilityand tendency of animals treated with sublethal doses of TCDD todefend their lowered body weight against external manipulations,by the irreversibility of TCDD-induced retardation in body weightgain and by the swift emergence and remarkable sensitivity ofthe neophobia-like response upon TCDD exposure. These featuresrender the wasting syndrome a potentially useful model, and TCDDan efficient tool, for physiological studies on the regulatory mech-anisms of energy balance.

The most resistant laboratory animals to the acute toxicity ofTCDD are hamsters and H/W rats. As seasonal animals, hamstersare genetically well-adapted to large variations in their bodyweight and may thereby tolerate the set-point-lowering effect ofTCDD. Interestingly, the behavioral response in H/W rats may alsobe unique: at very high doses of TCDD, they will often commence atotal fast which may last up to 11 consecutive days, and then rap-idly resume eating [331,467], whereas rats of TCDD-sensitivestrains keep on consuming small amounts of food until death.Since both hamsters and H/W rats possess AHRs that are remod-eled at the transactivation domain, the involvement of the AHRin the regulation of energy balance will be worth exploring.

The research of the wasting syndrome also has important bearingon the pathogenesis of diseases in which the control systems forbody weight are gravely affected such as anorexia nervosa and can-cer anorexia. The present view is that all the major toxic impacts ofdioxins are mediated by the AHR through its canonical signalingpathway. It seems, however, that the response pattern elicited byactivation of this pathway may depend on the ligand or the combina-tion of the AHR and its ligand (the same ligand might trigger a differ-ent response spectrum in different species due to variations in AHRstructure). In the future, this could pave the way to the developmentof compounds which might possess the potentially beneficial effectof dioxins on body weight (apparent lowering of the set-point level)but would be devoid of its toxicity. It is thus clear that there is still alot to explore in dioxins, the AHR and the central regulatory systemsof energy balance for years to come.

Acknowledgments

We thank Prof. Allan B. Okey for kindly allowing us to use one ofhis original figures of the AHR as the core for Fig. 3. This work wasfinancially supported by grants from the Academy of Finland(Grant Number 123345 [R.P.]) and from the Finnish Cultural Foun-dation, Regional fund of Northern Savo (S.L.).

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