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ACS WEBINARS™ January 31, 2013 Gender Bending Science: Impacts of Endocrine Disrupting Chemicals
Dr. Charles Tyler University of Exeter
Dr. Darren Griffin University of Kent
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Gender Bending Science: Impacts of Endocrine Disrupting Chemicals
Professor Charles R. Tyler
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Presentation Outline Our Dependence on Chemicals. Endocrine Disruption – What is it? Effects in Wildlife and Humans
Feminisation of Wild Fish Assessing Wider Health Implications of Exposure to Endocrine Disrupting Chemicals (Environmental Oestrogens) in Green Glowing Fish
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Our Dependence on Chemicals We use over 80 00 chemicals in products (a $3 trillion global enterprise) ..... plasticizers, fertilisers, pesticides, pharmaceuticals, etc.
Most of these enter can enter the bodies of humans through direct application (cosmetics) and/or via the food chain, in our drinking water or as aerosols. Similarly, these chemicals can enter the bodies of wildlife (and most notably for animals living in, or closely associated with aquatic environments which we will come to later) Some of these chemicals can build up (bioaccumulate) in our bodies potentially increasing any biological effects they might have. Pharmaceutical substances ($800 billion industry) are specifically designed to change physiological function
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Our Dependence on Chemicals and Some of Concern In Europe and the US there are Priority Substances for which we have concern because there is good evidence for adverse health effects (e.g. Lead, PCBs). Other Chemicals for which there is increasing health concern include: Industrial chemicals: Perfluoro octanoic acid (PFOAs) - found in the blood of 98% blood US citizens associated with elevated cholesterol and chronic kidney disease Polybrominated diphenyl ethers - Flame retardants associated with thyroid dysfunction Bisphenol A: Polycarbonate polymers and epoxy resins. Associated with various health disorders (e.g. obesity, reproduction)
Pharmaceutical substances: 17 alpha-ethinylestradiol (EE2), 17 beta-estradiol (E2), Diclofenac.
Endocrine Disrupting Chemicals
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Endocrine Disruption – What is it? Communication Systems: The nervous system together with the endocrine system make up the body’s major signalling pathways in all animals:
Endocrine = postal system Nervous = telephone network
A hormone is a chemical message that instructs a specific response
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Endocrine Disruption – What is it? Definition of an Endocrine Disrupter: a chemical (man-made or natural) that mimics a hormone(s) and disrupts growth, development and/or reproduction in an individual or its progeny…… HORMONE MIMIC OH
EDC a Stimulates Hormonal Response Hormone Receptor
OH
HORMONE ANTAGONIST
Native Hormone
EDC b Hormone Receptor
Inhibits Hormonal Response
* Enzyme systems which determine steroid synthesis, turnover, excretion dynamics 15
Evidence for Effects in Humans (Reproduction)
Falling sperm counts Increase in Hormone Dependent Cancers
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Evidence for Effects in Wildlife (Reproduction)
Most effects in animals living in or are closely associated with 17 aquatic environments.
Poll Question Why are aquatic animals more likely to be affected by Endocrine Disrupting Chemicals than terestrial animals? a.) Their hormone systems are more susceptible to the effects of chemicals b.) They are more likely to be exposed to them and at higher concentrations* c.) They accumulate chemicals in their bodies, but other animals do not d.) The cannot metabolise Endocrine Disrupting Chemicals 18
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Our Work on Endocrine Disruption: Feminisation of Wild Fish and its Causation in English Rivers
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Initial Observations Wastewater Treatment Works Effluents are Oestrogenic Vitellogenin (yolk)
Vitellogenin mg/ml
100000
***
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***
***
10000 1000 100 10 1 0.1 0.01
Purdom, C.E., Hardiman, P.A., Bye, V., Eno, N.C., Tyler, C.R. and Sumpter, J.P. (1994). Chemistry and Ecology. 8:275-285
Control Willington Consett Carlisle Winsford Burwarton Location of Sewage Treatment Works 20
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Sex in Fish is Plastic and can be altered by Exposure to Steroids Oogenesis Pharmacological doses of oestrogen
Genetic Males
Genetic Males or Females
‘Intermediate’ doses of steroids
Intersex
Genetic Females Pharmacological doses of androgen
Spermatogenesis 21
Sexual disruption in wild roach (Rutilus rutilus) in English Rivers Synopsis of findings … Intersex present at 44 (86%) of 51 sites
Percentage of sexually disrupted males at survey sites 0% 1–20%
Overall incidence of intersex in ‘males’ of 23%
21 – 40% 41 – 60% North East
Feminised reproductive duct
81–100%
Midlands
Oocytes in the testis Jobling,S., Williams, R., Johnson, A., Taylor, A., Gross-Sorokin, M., Nolan, M., Tyler, C.R., van Aerle, R.,Santos, E.M.,and Brighty, G. (2006). Environ Health Perspectives 114: 32-29
61 – 80%
Anglian
Thames Southern
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ALL FEMINISED RESPONSES seen in wild fish roach can be induced through controlled exposures to treated oestrogenic WwTW effluents
Vitellogenin Induction is induced in all fish life stages at 25%- 40% WwTW effluent for a 1 month exposure, 10% for 4 month exposure. Ovarian Cavity - induced in fish exposed during early life at 25% WwTW effluent (early life exposures). Intersex (oocytes in testis) - induced in fish at an exposure to 50% WwTW effluent (long term exposures). Rodgers-Gray, et al.,. (2000). Environ Sci Technol. 34:1521-1528. Rodgers-Gray, et al (2001). Environ Sci Technol. 35:(3) 462- 470. Liney, K.E., Jobling, S. Shears, J., Simpson. P.,Tyler, C.R. (2005) Environ Health Persp. 113 (10): 1299-1307 . Lange, A., Katsu, Y., R. Ichikawa, Chidgey, L. Iguchi, T.and. Tyler, C.R. (2009). EnvSciTechnol. 43 (4), 1219-1225 . Lange, A. * Paull, G.C., Hamilton, P.B., Iguchi, T. and Tyler C.R. (2011).. EnvSciTechnol. 45 (4): 1673–1679
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Wastewater Treatment Works effluent discharges into English Rivers: The scale of the issue Seasonal and annual variations in the proportional flow of STW effluent in an English river 80 70 60 50 40 30 20 10 0
% effluent
j
f m a m j
j a
s o
n d
Month of the year % effluent 100 90 80 70 60 50 40 30 20 10 0 90
91
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Estimated dilution ratios at point of discharges for major STWs (>10,000 PE) discharging to freshwaters 24
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Whodunit - Environmental oestrogens entering fish from WwTW effluents Mesocosms…. 2.5
E2
Control
E1
Absorbance (ABS)
2.0
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T im e (m inutes)
HO
E2
Exposed
3.0
EE2 E1 NP + NPnEO (n=1-4)
DHQ 2.5
OH
17βdihydroequilenin + (Equilenin)
Absorbance (ABS)
The oestrogenic activity of the test effluents measured
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T im e (m inutes) IO N T R A C E .M a x .S c a n = 1 3 0 9 # 3 0 :0 2 .4 2 . 1 0 0 8 0
NP NP1EO NP2EO
6 0
Intensity(%age)
Bile analysed to identify (anti-)oestrogenic compounds and their metabolites ………Enzymic hydrolysis –RPHPLC + yeast screens LC-NMR-MS/GC-MSMS
T o ta lIo nC u rre n t.M a x .In t.= 1 8 6 .5 9 8 8 5 .1 0 0 % In t.= 1 8 6 .5 9 8 8 5 .
4 0 2 0
NP3EO NP4EO
0 4 :0 0
6 :0 0
8 :0 0
1 0 :0 0
1 2 :0 0
1 4 :0 0
1 6 :0 0
1 8 :0 0
2 0 :0 0
R e te n tio nT im e
Gibson, R., Smith, M.D., Spary, C., Tyler, C.R., Hill, E.M. (2005). ES&T 39(8) 2461-2471 Tyler C.R., Spary, C, Gibson, R., Shears, J., Santos, E., Sumpter, J.P., Hill, E.M. (2005). ES&T 39 (8) 2599-2607 Tyler, C.R, Filby, A.L., Hill, E.M., Liney, K.E., Katsu, Y., Bickley, L.K., Lange, A., Winter, M., Gibson, R., Shears, J.A., Iguchi, T.(2009). ES&T. 43:3897-3904
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Poll Question # 2 When we consider chemical health protection in humans compared wildlife what is the difference in approach? a.) There is no difference, it essentially the same b.) There are internationally recognised test systems to protect for human health only
c.) Humans are protected at the level of the individual, whereas wildlife at the level of the population only *
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Breeding Consequences in Fish (Roach) of Exposure to Oestrogenic Wastewater Treatment Works Effluent ......i.e. Does it Matter?
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Breeding Impacts of the Intersex Condition in Roach Breeding trials with wild roach
Multiple tanks with 3 female and 6 ‘male’ wild-caught roach (13 tanks)
100% parentage achieved using exclusion
7 highly variable primers were developed and applied for parentage analysis (100% success)
Genotyped all parents and offspring (50-104 fry from each tank) 28
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Breeding Impacts of the Intersex Condition in Roach Intersex Index 0
‘Normal’ male
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Mild: 1-20 oocytes
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Moderate: 20-50 oocytes
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Severe: >50 oocytes
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Female
Oocytes
Harris, Hamilton, Runnalls, Jobling, Vinciotti, Henshaw, Hodgson. Coe, Tyler,. Sumpter (2010). EHP. 119:306–311
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Reproductive Success of Intersex Roach under Competitive Breeding LME model coefficient = -0.029, p < 0.0001
Reproductive success
0.6 0.5 0.4 0.3 0.2 0.1 0.0 0
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Intersex Index
There was a significant negative correlation between intersex index and reproductive success. Harris, Hamilton, et al ( 2010). EHP. 119:306–311
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Assessing Wider Health Implications of Exposure to Environmental Oestrogens The health effects of environmental oestrogens has been focused on reproduction (for obvious reasons). However, oestrogens play a role in many other physiological processes. Evidence for wider health impacts of environmental oestrogens in various vertebrates, including humans
Charles.R.Tyler
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Green Glowing Transgenic Fish for Understanding the Wider Health Effects of Environmental Oestrogens
(Xeno-)Estrogen
Primary Response :
Estrogen induces synthesis of Gal4ff protein
Amplification of the signal Secondary Response : Gal4ff protein induces synthesis of GFP
Estrogen Receptor
Gal4ffmRNA
3ERE GFPmRNA
GFP protein UAS
Okhyun Lee, Aya Takensono, Masa Tada, Charles R. Tyler* and Tetsuhiro Kudoh*- EHP. 2012
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Okhyun Lee, Aya Takensano, Masa Tada, Charles R. Tyler* and Tetsuhiro Kudoh* (2012)- EHP IN pRess
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ERE-Transgenic Zebrafish - Whole body profiling Identifies Target Tissues for Environmental Oestrogens
Control
The ERE-TG zebrafish are highly sensitive for detecting exposure to different environmental oestrogens
Zebrafish provide a model for bridging the gap when discerning possible health effects of EDCs between wildlife and humans. Okhyun Lee, Aya Takensono, Masa Tada, Charles R. Tyler* and Tetsuhiro Kudoh*- EHP. 2012
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Key collaborators and sponsors of the work presented:
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Thank you for listening! 35
ACS WEBINARS™ January 31, 2013 Gender Bending Science: Impacts of Endocrine Disrupting Chemicals
Dr. Charles Tyler University of Exeter
Dr. Darren Griffin University of Kent
Download the presentation ONE WEEK after webinar: http://acswebinars.org/gender-bending-chemicals Contact ACS Webinars™at
[email protected] 36
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2/11/2013
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Thursday, February 14, 2013
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2/11/2013
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