1 Hormone Disrupting Chemicals 1993: Sharpe and Skakkebæk publish the estrogen There’s nothing like a cold dip estrogen hypothesis “We argue that the increasing incidence of reproductive abnormalities in the human male may be related to increased oestrogen exposure in utero, and identify mechanisms by which this exposure could occur.” 100 150 Sperm cells 10 6 per ml 1930 1940 1950 1960 1970 1980 1990 0 50 2000 Topari et al, 1996 Intersex in British Perch populations Jobling et al. 1998 Jobling et al. 1998 Intersex Intersex Roach and reproduction? (Jobling et al, 2002)
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Hormone Disrupting Chemicals
1993: Sharpe and Skakkebæk publish the estrogen
There’s nothing like a cold dip
estrogen hypothesis
“We argue that the increasing incidence of reproductive abnormalities in the human male may be related to increased oestrogen exposure in utero, and identify mechanisms by which this exposure could occur.”
100
150
Sperm cells 106 per ml
1930 1940 1950 1960 1970 1980 19900
50
2000
Topari et al, 1996
Intersex in British Perch populations
Jobling et al. 1998Jobling et al. 1998
Intersex Intersex Roach and reproduction? (Jobling et al, 2002)
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Intersex Roach and reproduction?(Jobling et al, 2002)
The estrogen receptor domainsActivating function 1
Nuclear Localisationsignal
Activating function 2
DNA binding domain Hinge
Ligand binding domaindomain
Homology between Human and Rainbow trout ER
A/B: 20%
C: 92%
E: 60%
Hingeregion Agonist binding domain
Antagonist binding domain
Mathews et al. 2001
Hormone disruption mechanisms
• Hormone synthesis
• Hormone secretion
• Hormone transport• Hormone transport
• Receptor binding
• Receptor complex mediated transcription
• Hormone elimination
• -ve/+ve feedback loops
3
Possible sex homone disruption mechanisms:
EstrogenAndrogen
(Arukwe, 2001)
gAnti-EstrogenAnti-Androgen
Actually many of the really major stories in Ecotoxicology have in hindsight involved
endocrine disruption
Examples:
DDT• DDT• PCB’s• Dioxin• TBT
Cholesterol
Steroid Pathways Made Simple
P450 enzymesXenoandrogens
Progestogens Androgens
EstrogensCorticoids
Aromataseinhibitors
xenoestrogens
Imposex in the dogwhelk probably caused by elevated testosterone: a
result of aramatase inhibition?
Normal male Imposex female (4)
Imposex female (5/6)
Imposex Development in the Dog Whelk
Penis Penis Penis
Vas deferens
Prostate gland
Vas deferens
Capsule gland
Capsule gland
Nodule formation on the vas deferens
♀ Clean locality Egg capsules from plymouth bay
Stage 6 females are sterile
♀ From poluted location with aborted egg capsules
Egg capsules fused with mother shell
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Why the elevated testosterone levels?
1. Aromatase inhibition hypothesis (Bettin et al 1996;
Morcillo et al, 1998 a,b; Santos et al 2002)
2. Esterification hypothesis (Gooding et al, 2001, 2003;) total tesosterone level unchanged but esterified fraction reduced
3. Imbalance in Phase I and phase II enzymes resulting in a reduction in conjugation products and an increase in active androgen fractions (Ronis and Mason, 1996; Morcillo and Porte (1999)
Or imposex a result of a regulatory peptide? Testosterone levels are then a secondary effect
Oberdörstera and McClellan-Green, 2000
PMF=Penis modulating factorASO=Accessory sex organT=TestosteroneE2=Estrogen
Normal female Partly masculinised female
AndrogenEffectsmosquitofish caught below an american Pulp mill
Female with advanced masculinisation
Normal male
Androgens or aramatase inhibition??
Parks et al,2001
Paper-millmill
Initial stages of female masculinisation Toft et al, 2004
Feminization is quantified by counting segments(Parks et al 2001)
Reference females
R f lP ll t d f l Reference malesPolluted females
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Downstream sites caused greater AR-binding inhibition than 1micromolar flutamide
1nM
Parks et al, 2001
Downstream sites caused similar AR-mediated gene expression as DHT
Flutamide
Parks et al, 2001
The chemical induces AR migration into the nucleus
Dexamethasonepotent glucocorticoidreceptoragonist
Masculinization is not a result of corticosteroid receptor activity
Parks et al, 2001
Brain and ovarian aromatase activity is higher in fish exposed to pulp mill