UNIVERSITATIS OULUENSIS MEDICA ACTA D D 1254 ACTA Mikko A. J. Finnilä OULU 2014 D 1254 Mikko A. J. Finnilä BONE TOXICITY OF PERSISTENT ORGANIC POLLUTANTS UNIVERSITY OF OULU GRADUATE SCHOOL; UNIVERSITY OF OULU, FACULTY OF MEDICINE, INSTITUTE OF BIOMEDICINE, DEPARTMENT OF ANATOMY AND CELL BIOLOGY; DEPARTMENT OF MEDICAL TECHNOLOGY; NATIONAL INSTITUTE FOR HEALTH AND WELFARE, DEPARTMENT OF ENVIRONMENTAL HEALTH; UNIVERSITY OF EASTERN FINLAND, FACULTY OF SCIENCE AND FORESTRY, DEPARTMENT OF ENVIRONMENTAL SCIENCE; CRANFIELD UNIVERSITY, CRANFIELD DEFENCE AND SECURITY, CRANFIELD FORENSIC INSTITUTE
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UNIVERSITY OF OULU P .O. B 00 F I -90014 UNIVERSITY OF OULU FINLAND
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SCIENTIAE RERUM NATURALIUM
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EDITOR IN CHIEF
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ISBN 978-952-62-0508-3 (Paperback)ISBN 978-952-62-0509-0 (PDF)ISSN 0355-3221 (Print)ISSN 1796-2234 (Online)
U N I V E R S I TAT I S O U L U E N S I S
MEDICA
ACTAD
D 1254
ACTA
Mikko A
. J. Finnilä
OULU 2014
D 1254
Mikko A. J. Finnilä
BONE TOXICITY OF PERSISTENT ORGANIC POLLUTANTS
UNIVERSITY OF OULU GRADUATE SCHOOL;UNIVERSITY OF OULU, FACULTY OF MEDICINE,INSTITUTE OF BIOMEDICINE,DEPARTMENT OF ANATOMY AND CELL BIOLOGY;DEPARTMENT OF MEDICAL TECHNOLOGY;NATIONAL INSTITUTE FOR HEALTH AND WELFARE,DEPARTMENT OF ENVIRONMENTAL HEALTH;UNIVERSITY OF EASTERN FINLAND, FACULTY OF SCIENCE AND FORESTRY,DEPARTMENT OF ENVIRONMENTAL SCIENCE;CRANFIELD UNIVERSITY, CRANFIELD DEFENCE AND SECURITY,CRANFIELD FORENSIC INSTITUTE
A C T A U N I V E R S I T A T I S O U L U E N S I SD M e d i c a 1 2 5 4
MIKKO A. J. FINNILÄ
BONE TOXICITY OF PERSISTENT ORGANIC POLLUTANTS
Academic dissertation to be presented with the assent ofthe Doctora l Train ing Committee of Health andBiosciences of the University of Oulu for public defence inAuditorium A101 of the Department of Anatomy andCell Biology (Aapistie 7 A), on 8 August 2014, at 12 noon
Supervised byProfessor Juha TuukkanenProfessor Timo JämsäProfessor Matti Viluksela
Reviewed byProfessor Yrjö T. KonttinenProfessor Reijo Lappalainen
ISBN 978-952-62-0508-3 (Paperback)ISBN 978-952-62-0509-0 (PDF)
ISSN 0355-3221 (Printed)ISSN 1796-2234 (Online)
Cover DesignRaimo Ahonen
JUVENES PRINTTAMPERE 2014
OpponentAssociate Professor Monica Lind
Finnilä, Mikko A. J., Bone toxicity of persistent organic pollutants. University of Oulu Graduate School; University of Oulu, Faculty of Medicine, Institute ofBiomedicine, Department of Anatomy and Cell Biology; Department of Medical Technology;National Institute for Health and Welfare, Department of Environmental Health; University ofEastern Finland, Faculty of Science and Forestry, Department of Environmental Science;Cranfield University, Cranfield Defence and Security, Cranfield Forensic InstituteActa Univ. Oul. D 1254, 2014University of Oulu, P.O. Box 8000, FI-90014 University of Oulu, Finland
Abstract
Persistent organic pollutants (POPs), especially dioxin-like chemicals, have been shown to haveadverse effects on skeleton and these effects are likely to be mediated via the aryl hydrocarbonreceptor (AHR). In spite of the extensive research, the characteristics of developmental effects ofPOPs are poorly known and the role of AHR in POP bone toxicity and skeletal development ingeneral.
In this project changes in bone morphology and strength as well as tissue matrix mechanics arestudied by applying state of the art biomedical engineering methods. This allows understanding ofthe effects of dioxins exposure and AHR activity on the development and maturation ofextracellular matrix in musculoskeletal tissues from a completely new perspective, and therebyimproving the health risk assessment of POPs.
In the present study skeletal properties of rats exposed maternally to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), Northern Contaminant Mixture (NCM) and Aroclor 1254(A1254) were studied for cross-sectional morphometric and biomechanical properties, and datawere analysed with benchmark dose modelling. In addition, extracellular matrix properties wereanalysed using nanoindentation. Similar measurements were performed for adult wild-type andAHR-null mice after TCDD exposure. The same animals were also analysed for microstructuralchanges using micro-computed tomography and their bone cell activity was estimated from serummarkers and gene expression.
Analyses show decreased bone length and cross-sectional properties with consequentlydecreased bone strength. On the other hand, an increased trabecular bone mineral density inresponse to NCM and A1254 was observed. In addition, bone matrix properties indicated delayedmaturation or early senescence after maternal or adult exposure, respectively. The AHR is mainlyresponsible for bone toxicity of dioxin-like compounds and plays a role in bone development. Thisis likely due to disturbed bone remodeling as indicated by altered serum markers and geneexpression. Overall these results indicate that POPs decrease bone strength, but the interpretationis difficult as there is more trabecular bone within cortical bone with compromised quality andincreased porosity.
Finnilä, Mikko A. J., Pysyvien orgaanisten yhdisteiden luutoksisuus. Oulun yliopiston tutkijakoulu; Oulun yliopisto, Lääketieteellinen tiedekunta, Biolääketieteenlaitos, Anatomia ja solubiologia; Lääketieteen tekniikka; Terveyden ja hyvinvoinninlaitos,Ympäristöterveyden osasto; Itä-Suomen yliopisto, Luonnontieteiden ja metsätieteidentiedekunta, Ympäristötieteen laitos; Cranfield University, Cranfield Defence and Security,Cranfield Forensic InstituteActa Univ. Oul. D 1254, 2014Oulun yliopisto, PL 8000, 90014 Oulun yliopisto
Tiivistelmä
Altistumisen pysyville orgaanisille ympäristökemikaaleille on todettu heikentävän luustoa.Dioksiinien ja dioksiininkaltaisten yhdisteiden vaikutusten on havaittu välittyvän aryylihiilivety-reseptorin (AHR) välityksellä. Huolimatta pitkään kestäneestä tutkimuksesta POP-yhdisteidensikiönkehityksen aikaisen altistuksen vaikutukset ja etenkin niiden mekanismit ovat edelleenhuonosti tunnettuja, samoin kuin AHR:n osuus POP-yhdisteiden luutoksisuudessa ja luustonkehityksessä ylipäätään.
Tässä työssä tutkittiin luuston rakenteellisia ja mekaanisia ominaisuuksia niin perinteisilläkuin uusimmilla biolääketieteen tekniikan menetelmillä. Tutkimuksen tavoitteena on saada uut-ta tietoa POP-altistuksen ja AHR-aktiivisuuden vaikutuksista luuston kehitykseen ja luukudok-sen ikääntymisprosesseihin, mikä edesauttaa kyseisten yhdisteiden riskinarviointia.
Tutkimuksissa altistettiin kantavia rottaemoja 2,3,7,8-tetraklooridibenzo-p-dioksiinille(TCDD), pohjoiselle saasteseokselle ja kaupalliselle Arokloori 1254 PCB-seokselle. Sikiönkehi-tyksen aikana altistuneiden jälkeläisten luuston poikkileikkauksen morfologia ja biomekaanisetominaisuudet mitattiin ja tulokset mallinnettiin vertailuannoksen määrittämiseksi. LisäksiTCDD-altistettujen rottien luustomatriisin ominaisuuksia selvitettiin nanoindentaatiomenetel-mällä. Samaa menetelmää käytettiin myös aikuisiässä TCDD:lle altistettujen villityypin hiirtenja AHR-poistogeenisiten hiirten tutkimiseen. Näiden hiirten luuston hienorakennetta mitattiinmyös korkean resoluution mikro-tietokonetomografialla ja niiden luusolujen aktiivisuutta tutkit-tiin seerumin biomarkkerien ja luun muodostumiseen osallistuvien geenien ekspressiotasojenavulla.
Sikiönkehityksen aikainen altistuminen pohjoiselle saasteseokselle ja Arokloori 1254:llehidasti luiden pituuskasvua. Lisäksi luiden poikkileikkauspinta-alat olivat pienentyneet jamekaaniset ominaisuudet heikentyneet. Toisaalta hohkaluun määrä oli lisääntynyt altistumisenseurauksena.
Myös sikiönkehityksen aikainen altistuminen TCDD:lle hidasti luukudoksen kypsymistä jajohti aikuisiällä luukudoksen ennenaikaiseen vanhenemiseen. AHR:llä oli päärooli ainakinaikuisiän vaikutusten ilmenemiselle ja reseptorilla vaikutti olevan rooli luuston kehityksessä yli-päätään. Seerumin biomarkkereiden ja geeniekspression muutosten perusteella nämä vaikutuk-set johtuvat todennäköisesti luuston uusiutumisen häiriöistä. Yhteenvetona voidaan todeta, ettäPOP-yhdisteet heikentävät luustoa, mutta tämän ilmiön diagnosoiminen on hankalaa, koska huo-nolaatuisen kuoriluun sisällä hohkaluun määrä on lisääntynyt.
The thesis consists of four original publications that are referred to in the text by
their Roman numerals (I-IV). Additional yield and trabecular bone mineral
density data related to studies II and III are also included.
I Finnilä MA, Zioupos P, Herlin M, Miettinen HM, Simanainen U, Håkansson H, Tuukkanen J, Viluksela M & Jämsä T (2010) Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure on bone material properties. J Biomech 43: 1097–1103.
II Elabbas LE, Finnilä MA, Herlin M, Stern N, Trossvik C, Bowers WJ, Nakai J, Tuukkanen J, Heimeier RA, Åkesson A & Håkansson H (2011) Perinatal exposure to environmental contaminants detected in Canadian Arctic human populations changes bone geometry and biomechanical properties in rat offspring. J Toxicol Environ Health A 74: 1304–1318.
III Elabbas LE, Herlin M, Finnilä MA, Rendel F, Stern N, Trossvik C, Bowers WJ, Nakai J, Tuukkanen J, Viluksela M, Heimeier RA, Akesson A & Håkansson H (2011) In utero and lactational exposure to Aroclor 1254 affects bone geometry, mineral density and biomechanical properties of rat offspring. Toxicol Lett 207: 82–88.
IV Herlin M*, Finnilä MAJ*, Zioupos P, Aula A, Risteli J, Miettinen HM, Jämsä T, Korkalainen M, Tuukkanen J, Håkansson H & Viluksela M (2013) New insights to the role of aryl hydrocarbon receptor in bone phenotype and in dioxin-induced modulation of bone microarchitecture and material properties. Toxicol Appl Pharmacol 273(1): 219–226.
*Equal contribution
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15
Contents
Abstract
Tiivstelmä
Acknowledgements 7
Abbreviations and symbols 7
List of original publications 13
Contents 15
1 Introduction 17
2 Review of the literature 19
2.1 Bone ........................................................................................................ 19
2.2 Bone tissue formation and (re)modeling ................................................. 19
2.3 Bone composition and extracellular matrix physics ................................ 23
2.4 Bone morphology .................................................................................... 25
Tgfb2), cell growth and differentiation (Fgf1), transcription factors and regulators
(Msx1) and cell adhesion molecules (Col12a1).
WT:C
TRL
WT:T
CDD
KO:CTRL
KO:TCDD
WT:C
TRL
WT:T
CDD
KO:CTRL
KO:TCDD
0.0
0.5
1.0
1.5
2.0
2.5
***
PIN
P/C
TX
61
Control AHR ablated mice differed for two genes as compared with wild type
controls. One up-regulated was associated with extracellular matrix proteins and
down-regulated with skeletal development (Ahsg). The down-regulated gene was
lower also both in TCDD-exposed Ahr+/+ and Ahr-/- mice.
For Ahr-/- mice, TCDD-exposure altered the expression of only five genes.
Three of these were up-regulated and associated with skeletal development
(Tfip11, Col2a1), bone mineral metabolism (Col2a1) and extracellular matrix
proteins (Col10a1), while the two down-regulated genes were associated with
skeletal development (Ahsg) and with cell growth and differentiation (Vegfb).
5.7 Dose modelling
For NCM the pQCT and biomechanical variable with highest mean square values
got the lowest BDs indicating highest sensitivity. At PND 35 the 5% decrease was
estimated to 0.8 and 1.2 mg/kg bw/d for maximal breaking force and stiffness of
femoral diaphysis, while for the femoral the neck maximal breaking force
corresponding dose was 1.4 mg/kg bw/d. Also the strength estimates from pQCT
got low BD values being 0.9 and 1.1 mg/kg bw/d for polar moment of inertia and
polar strength strain index. Interestingly, the tibial length and morphological
values had higher BD estimates being 3.2, 1.6, 2.2 and 4.8 mg/kg bw/d for tibial
length, cortical area, cortical thickness and periosteal circumference, respectively.
All BD estimates had BD/BDL within the well tolerable range of 1.2–1.5. It is
possible to extract also maximal response from BD analyses. Generally maximal
response decrease with age (publication II, table 2B), while BD values first
decreased and then increased at PND 77 and PND 350 respectively, while the
BD/BDL were highest at PND 77 compared to other age points.
The TEQ for the used A1254 was 0.123 µg/kg bw/d with major contributions
from dioxin-like PCB congeners 126, 118 and 105 by 46%, 29%, and 12%,
respectively. Thus in this experiment the total dose of A1254 was estimated to
5.289 µg/kg bw. When the measured responses of the various bone parameters to
this dose of A1243 were compared against dose models of classical TCDD
exposure, the equivalents settled between 0.83–1.22µg/kg bw giving a range of
16–23% against the theoretical TEQ (publication III, table 4).
62
63
6 Discussion
The main goal of this study was to better understand the effects of POPs in bone
strength and morphology and the role of AHR in bone toxicity and skeletal
development at multiple hierarchical levels, thus bringing new mechanistic data
for environmental health risk assessment. This is crucial since according to the
WHO (WHO 2000) developmental defects are the most sensitive toxic endpoint
of dioxin-like compounds, and at current exposure levels the safety margin for
these effects is very narrow and simultaneous exposure to a wide variety of
different chemicals emphasize the potential significance of mixture effects (e.g.
additivity or synergism) that are dismissed when studying single chemicals
(WHO 2013).
6.1 Novel methods in bone toxicology
Part of the research novelty arises in applying recent biomedical engineering
methodologies in such an exciting field as environmental toxicology. The added
scientific value is visually clear when comparing pQCT and µCT images to each
other of the same sample Fig. 12.
Although pQCT provides a better picture of the skeletal changes than DXA
and captures some key features as with µCT (total area, cortical area) (Schmidt et
al. 2003) the method has problems separating the endosteal border of bone thus
leading to potential underestimation of BMD with increased trabecular bone
volume fraction and medullary area. Also the cortical porosity is mixed in cortical
BMD due to partial volume effects, while µCT can provide separate estimates of
TMD and cortical porosity.
Where traditional mechanical testing can be used to quantify mechanical
properties of whole bone, nanoindentation characterizes the bone material
properties, describing the bone matrix quality. These qualitative properties
contribute to overall bone strength and can make bones brittle, harder and stiffer.
It was noticed that these properties are inter-related and appear to follow BMC.
Unfortunately by the time of study I, we did not have access to µCT equipment,
and we cannot compare TMD in that study.
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Fig. 12. Measurement positions indicated in scout view for both cortical and
trabecular bone for pQCT (two yellow dotted lines) and µCT (between two dotted black
lines). The µCT imaging provides a more complete picture of changes based on
morphological information from longer length that can be used for 3D analyses and
visualization.
Even if we utilized latest technologies to show effects of TCDD on intrinsic
properties of extracellular bone matrix and true 3D volumetric analysis of
trabecular bone and cortical porosity, there are still some improvements that
should be implemented in future studies. The technical limitation in our
nanoindentation studies was the use of dried samples, which has been often the
case (Lewis & Nyman 2008), partly due to equipment requirements, partly due to
the practical difficulty in preparing moist bone specimens without embedding,
especially from animals as small as mice. However, it has been shown, that
strontium ranelate induced improvements in material properties were more
pronounced in samples stored in a physiological solution as compared to dried
samples, where the effect disappeared (Ammann et al. 2007). Thus, it is tempting
to speculate that the effects observed in this study are more likely an
underestimation of real effects that should be probed in physiological conditions.
65
Further, the porosity analyses here were performed from images with
resolution of 5 µm, although it has recently been suggested that a resolution of as
low as 2 µm should be used for murine vascular structures (Palacio-Mancheno et
al. 2014). The same study demonstrated that osteocyte lacunas could be
quantified and visualized at resolutions of 1µm or better.
6.2 Model compound and genetic model studies
Study I showed delayed maturation after maternal TCDD exposure. More
specifically, bone matrix became more ductile, softer and less able to store energy
than control bones. Based on the correlation between intrinsic material properties
and mineralization parameters we suspect these changes are mainly due to
decreased mineralization. However, the role of the organic part cannot be
excluded since these changes are also supported by notification of previously
reported decrease in water and collagen content (Lind et al. 2000b). In this case
the increased mature cross-links could not provide improved strength and the role
of hydroxyproline in bone strength is still unknown. On the other hand, these
results are also supported by previously reported increased amount of osteioid
(Lind et al. 1999), while the time course is surprising. In humans ERα
inactivation has been shown to delay bone maturation (Quaynor et al. 2013,
Smith et al. 1994).
The toxic effects of TCDD and other dioxin-like compounds are mostly
mediated through AHR signaling. Thus, the role of AHR was studied in normal
skeletal development and dioxin toxicity at various hierarchical levels. Bone
remodeling was increased in Ahr-/- mice and they presented a skeletal phenotype
with softer and more elastic bones. Interestingly, also the bones of CA-AHR mice
were less stiff and more bendable, which most likely reflects to material level
alterations as they had also increased periosteal circumference (Wejheden et al.
2010). Ahr-/- also showed increased trabecular bone volume fraction and the
number of trabeculae were higher in these mice, similar to another recent report
(Iqbal et al. 2013). The previous studies have indicated reduced osteogenesis by
RANK-L, BaP (Iqbal et al. 2013) and less active osteoblastic cells (Korkalainen
et al. 2009, Ryan et al. 2007) in absence of AHR in vitro. However, in our Ahr-/-
mice high serum CTX indicated increased osteoclastic resorption, which might
increase osteoblastic activity through coupling. Furthermore, dioxin
administration had hardly any effects on the bone properties of the Ahr-/- mice.
66
In Ahr+/+ mice, dioxin exposure caused increased cortical porosity and a
strong anabolic effect on trabecular bone formation. Here porosity analysis
consisted mainly of blood vessels (Haversian and Volkman channels), but might
include some collagen fibers from tendon attachment at lateral side. However,
still it would be logical that osteoclastic resorption would take place in close
proximity to blood vessels and with reduced bone formation the filling of cavity
would not be complete. These effects appeared only in females. Additionally,
females showed reduced maximal and yield strengths. Reduced yield strength
indicates increased microfracture susceptibility and is probably due the increased
hardness and reduced elasticity of tissue. Generally these results indicate early
onset of skeletal senescence further supported by an observed reduced remodeling
ratio.
Similarly to TCDD exposed Ahr+/+ mice, increases in trabecular bone volume
fraction and decreased cortical thickness have been reported in ERα-/- mice
(Lindberg et al. 2001, Lindberg et al. 2002, Sims et al. 2002). Furthermore there
is evidence that AHR activation could cause ERα (Beischlag & Perdew 2005) and
ERβ (Ruegg et al. 2008) transrepression supporting the view that phenotype
could be due ER inactivation (but not antiestrogenic). However, it should be
pointed out that there are other animal models with similar skeletal phenotype e.g.
IL11α1-/- and IL6-/- (Sims et al. 2005). In PCB126 exposed adult female rats an
increase in expression of ER mRNAs has been reported with no effect on the ER
content (Lind et al. 2004).
6.3 Towards studies with naturally occurring POP mixtures
As most toxicological studies have been previously based on exposure to model
compounds, such as TCDD and individual PCB congeners, here we studied two
mixtures that resemble more of the existing POP body burden of human
populations (Van Oostdam et al. 2005). The used mixtures NCM and A1254
included 28 and 21 separate chemicals, respectively, while they did not include
the most potent PCDD/Fs. Still used mixtures appeared to have skeletal toxicity
compatible with the profile of bone changes elicited by perinatal TCDD and / or
PCB exposure described in chapter Table 1. Also the both mixtures increased
Trab.BMD later at PND 77.
Effects of A1254 were somewhat lower than what could be estimated via
TEQ estimation based on the assumption of additivity of effects of individual
chemicals. Recently it has been suggested that various types of POPs might have
67
even synergistic effects (Koskela et al. 2012). This will set a huge challenge for
chemical risk assessment, since there are over 800 chemicals that could
potentially disturb the endocrine system (WHO 2013) and thus the skeletal
system.
In the population of the Canadian Arctic, 2- to 10-fold higher levels of
environmental contaminants have been shown than in general populations living
in regions further south (Van Oostdam et al. 1999). Recently it has been shown
that POP intake in these communities exceeds the Canadian provisional tolerable
daily intake, and in one of these communities, 7% of young women exceed the
Health Canada tolerable serum level of 5 μg/L total PCB as A1254 (AMAP 2009).
However, in population based studies the correlation between skeletal properties
and POP burden has been mild (Paunescu et al. 2013b) or absent (Paunescu et al.
2013a) in both Canada and Greenland (Cote et al. 2006).
6.4 Translation of findings to human health
There have been a few known major chemical accidents or incidents that have
heavily increased POP exposure of affected populations. In Turkey the use of
HCB for treating grain in 1955–1959 resulted in HCB-exposure via contaminated
food and caused a porphyria cutanea tarda epidemic in the affected population
(Peters et al. 1987). Various skeletal manifestations have been observed within
this population including arthritis and osteomyelitis soon after exposure (Dean
1961), small hands, peripheral arthritis with osteoporosis and joint space
narrowing even decades after exposure (Gocmen et al. 1989, Peters et al. 1987).
Later in 1968 in northern Japan, ingestion of PCB and PCDF contaminated
rice oil (Yusho) lead to fetal PCB syndrome including abnormal calcification of
skull and feet malformation with dark pigmentation, gingival hyperplasia and
exophthalmic edematous eyes (Yamashita & Hayashi 1985). A recent study
showed a lack of association between serum PCB, PCQ, PCDF and BMD and
CTX (Yoshimura et al. 2009). However, there has been about 120-fold decrease
in serum TEQ between 1969 and 2007 (Masuda 2009).
Finally, a major incident took place in Seveso, Italy on 10th of July 1976,
where an explosion in a chemical factory resulted in a release of up to 30 kg of
TCDD, spread over the surrounding 18 km2 area. It has been recently reported
that DXA bone scans did not reveal adverse effects on bone health 32 years later
in women who were < 20 years old during the explosion (Eskenazi et al. 2014).
68
There are reports showing relationships between exposure to various POPs
and altered skeletal parameters. DDE (Beard et al. 2000) and PCB28 have been
associated with decreased skeletal mass, while PCB28 and γ-HCH with increased
mass (Glynn et al. 2000). Often, when adjusting with confounding factors the
effect dilutes and is no longer statistically significant. Thus the skeletal toxicity of
POPs has been mild or difficult to detect.
However, the socioeconomic burden of reduced bone strength arises from the
fractures rather than osteoporosis per se. Increased fracture incidence was found
in fishermen and their wives exposed to POP through dietary intake of fatty fish
from the Baltic sea (Alveblom et al. 2003). This causality was not present in a
questionnaire based study on the following year (Wallin et al. 2004). Thus the
attempts to correlate clinical findings with POP exposure levels for predicting
fracture risk are necessary. DXA based BMD has been the gold standard for
fracture risk assessment, but evidence shows that BMD is not a sufficient tool to
indicate patients at risk of fracture (Schuit et al. 2004, Stone et al. 2003). Also the
currently used ultrasound parameters mainly reflect the overall bulk properties
(Gluer 2007). Furthermore, the animal models in these studies present often with
weaker and smaller bones, however with increased trabecular bone fraction. This
indicates that POPs decrease bone strength, but in such a way that they are
difficult to diagnose due to increased amount of trabecular bone inside cortical
bone with poorer quality and smaller dimensions. For these reasons it is not
surprising that in some studies no statistically significant associations between
BMD/ultrasound and POP were found (Beard et al. 2000, Cote et al. 2006,
Eskenazi et al. 2014, Glynn et al. 2000, Hodgson et al. 2008, Paunescu et al.
2013a, Paunescu et al. 2013b, Rignell-Hydbom et al. 2009, Wallin et al. 2005).
Therefore in future more advanced diagnostic tools such as high resolution pQCT
should be used to study skeletal properties in POP exposed populations to
elucidate fracture risk in adult population. Some studies showed weak association
with POP burden and skeletal properties but they disappeared after various
adjustments for all possible confounding factors (Cote et al. 2006, Glynn et al.
2000, Rignell-Hydbom et al. 2009, Wallin et al. 2005). Age alone is such a strong
predictor of skeletal properties. In our NCM study the age explained about 200
times higher correlation to radiological and biomechanical parameters compared
to treatment. However, it should be realized that the treatment was relatively short
as NMC exposure was stopped at PND 23, whereas the whole study period
extended over 360 days.
69
However, it should be pointed out that the skeletal manifestations were
dependent on exposure timing. In adults TCDD exposure leads to decreased
diaphyseal bone size, increased porosity and brittleness of tissue. The maternal
exposure, on the other hand, delayed maturation of bone tissue increasing a risk
of green stick fractures. This implies that early POP exposure might increase bone
ductility and later brittleness. Interestingly, in all studies increased trabecular bone
quantity was observed. Nevertheless, in all cases POP exposure decreased bone
strength and it would be surprising if this would not be the case in humans as well.
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71
7 Conclusions
The main goal of the thesis was to understand the effects of POPs on bone
strength and morphology, and the role of AHR in bone toxicity and skeletal
development. Based on the results of this study, it can be concluded that;
1. Developmental TCDD does not alter bone matrix properties at the level that
they would contribute to decreased bone strength. However, TCDD exposure
was shown to delay bone matrix maturation.
2. Exposure to the NCM decreases bone size and strength at relevant but
relatively high dose levels. NCM was observed to increase Trab.BMD.
3. PCB mixture A1254 causes similar changes as TCDD exposure leading to
shorter, thinner and weaker bones in juvenile rats. Again as in the NCM study
Trab.BMD was observed to be increased in adult animals after discontinued
exposure.
4. The AHR receptor has a major role in TCDD induced bone toxicity and bone
homeostasis. A new insight was gained for cortical porosity and tissue
senescence as well as increased trabecular bone quantity.
5. In general the opposite effects on trabecular and cortical bone compartments
demonstrate a need for a new view when analyzing radiological data from
humans.
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Original publications
I Finnilä MA, Zioupos P, Herlin M, Miettinen HM, Simanainen U, Håkansson H, Tuukkanen J, Viluksela M & Jämsä T (2010) Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure on bone material properties. J Biomech 43: 1097–1103.
II Elabbas LE, Finnilä MA, Herlin M, Stern N, Trossvik C, Bowers WJ, Nakai J, Tuukkanen J, Heimeier RA, Åkesson A & Håkansson H (2011) Perinatal exposure to environmental contaminants detected in Canadian Arctic human populations changes bone geometry and biomechanical properties in rat offspring. J Toxicol Environ Health A 74: 1304–1318.
III Elabbas LE, Herlin M, Finnilä MA, Rendel F, Stern N, Trossvik C, Bowers WJ, Nakai J, Tuukkanen J, Viluksela M, Heimeier RA, Akesson A & Håkansson H (2011) In utero and lactational exposure to Aroclor 1254 affects bone geometry, mineral density and biomechanical properties of rat offspring. Toxicol Lett 207: 82–88.
IV Herlin M, Finnilä MAJ, Zioupos P, Aula A, Risteli J, Miettinen HM, Jämsä T, Korkalainen M, Tuukkanen J, Håkansson H & Viluksela M (2013) New insights to the role of aryl hydrocarbon receptor in bone phenotype and in dioxin-induced modulation of bone microarchitecture and material properties. Toxicol Appl Pharmacol 273(1): 219–226.
Reprinted with permission from Elsevier (I, III, IV) and Taylor & Francis (II).
Original publications are not included in the electronic version of the dissertation.
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1250. Prunskaite-Hyyryläinen, Renata (2014) Role of Wnt4 signaling in mammalian sexdetermination, ovariogenesis and female sex duct differentiation
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