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Gender Bending Science:
Impacts of Endocrine Disrupting Chemicals
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ACS WEBINARS™ January 31, 2013
Dr. Darren Griffin
University of Kent Dr. Charles Tyler
University of Exeter
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Professor Charles R. Tyler
Gender Bending Science:
Impacts of Endocrine Disrupting Chemicals
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2/11/2013
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Assessing Wider Health Implications of
Exposure to Endocrine Disrupting Chemicals
(Environmental Oestrogens) in Green Glowing
Fish
Feminisation of Wild Fish
Presentation Outline
Our Dependence on Chemicals.
Endocrine Disruption – What is it?
Effects in Wildlife and Humans
11
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.
Our Dependence on Chemicals
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 12
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Pharmaceutical substances: 17 alpha-ethinylestradiol (EE2), 17 beta-estradiol (E2), Diclofenac.
Endocrine Disrupting Chemicals
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).
Our Dependence on Chemicals and Some of Concern
Other Chemicals for which there is increasing health concern include:
Bisphenol A: Polycarbonate polymers and epoxy resins. Associated
with various health disorders (e.g. obesity, reproduction)
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
Industrial chemicals:
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Endocrine = postal system
A hormone is a chemical message
that instructs a specific response
Communication Systems: The nervous system together with the endocrine
system make up the body’s major signalling pathways in all animals:
Nervous = telephone network
Endocrine Disruption – What is it?
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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 Receptor
OH
OH EDC a
Stimulates Hormonal Response
HORMONE MIMIC
Hormone Receptor
Inhibits Hormonal Response
EDC b
HORMONE ANTAGONIST Native Hormone
* Enzyme systems which determine steroid synthesis, turnover, excretion dynamics
Endocrine Disruption – What is it?
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Falling sperm counts
Increase in Hormone
Dependent Cancers
Evidence for Effects in Humans (Reproduction)
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Evidence for Effects in Wildlife (Reproduction)
Most effects in animals living in or are closely associated with
aquatic environments. 17
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
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Our Work on Endocrine Disruption:
Feminisation of Wild Fish and its Causation
in English Rivers
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Control Burwarton
V
itello
gen
in m
g/m
l
Willington Consett Carlisle Winsford 0.01
0.1
1
10
100
1000
10000
100000
Location of Sewage Treatment Works
Wastewater Treatment Works
Effluents are Oestrogenic
Vitellogenin (yolk)
*** *** *** ***
Initial Observations
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 20
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Genetic
Males
Pharmacological
doses of oestrogen
Genetic
Females
Genetic
Males or
Females
Pharmacological
doses of androgen
Oogenesis
Spermatogenesis
‘Intermediate’
doses of steroids
Sex in Fish is Plastic and can be altered by
Exposure to Steroids
Intersex
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0%
1–20%
21 – 40%
41 – 60%
61 – 80%
81–100%
North East
Midlands
Thames
Southern
Anglian
Synopsis of findings …
Intersex present at 44
(86%) of 51 sites
Overall incidence of
intersex in ‘males’ of 23%
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
Sexual disruption in wild roach (Rutilus rutilus)
in English Rivers
Oocytes in the testis
Feminised reproductive duct
Percentage of sexually
disrupted males at
survey sites
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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
ALL FEMINISED RESPONSES seen in wild fish roach can be
induced through controlled exposures to treated oestrogenic
WwTW effluents
23
Seasonal and annual variations in the proportional
flow of STW effluent in an English river
0
10 20 30 40 50 60 70 80 90
100
90 91 92 93 94 95 96
Year
% effluent
0
10
20
30
40
50
60
70
80
j f m a m j j a s o n d
% effluent
Month of the year
Wastewater Treatment Works effluent discharges
into English Rivers:
Estimated dilution ratios at point of
discharges for major STWs (>10,000 PE)
discharging to freshwaters
The scale of the issue
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Whodunit - Environmental oestrogens entering fish from
WwTW effluents
0.0
0.5
1.0
1.5
2.0
2.5
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55 57 59
Time (minutes)
Ab
sorb
an
ce (
AB
S)
E2 E1
The oestrogenic activity of
the test effluents measured
Bile analysed to identify (anti-)oestrogenic compounds
and their metabolites ………Enzymic hydrolysis –RP-
HPLC + yeast screens LC-NMR-MS/GC-MSMS
Mesocosms….
Bile
0.5
1.0
1.5
2.0
2.5
3.0
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55 57 59
Time (minutes)
Ab
sorb
an
ce (
AB
S)
NP +
NPnEO
(n=1-4)
E2 EE2 E1
DHQ
ION TRACE. Max.Scan=1309#30:02.42.
Total Ion Current. Max.Int.=186.59885. 100% Int.=186.59885.
Retention Time
4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
Intensity (%age
)
0
20
40
60
80
100
NP NP1EO
NP2EO NP3EO
NP4EO
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
17β-
dihydroequilenin +
(Equilenin)
OH
HO
Control
Exposed
25
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 *
Poll Question # 2
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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 trials
with wild roach
7 highly variable primers were developed
and applied for parentage analysis (100%
success)
Genotyped all parents and
offspring (50-104 fry from
each tank)
100% parentage achieved using exclusion
Multiple tanks with 3 female and 6
‘male’ wild-caught roach (13 tanks)
Breeding Impacts of the Intersex Condition in Roach
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Intersex Index
Mild: 1-20 oocytes
Severe: >50 oocytes
Female
‘Normal’ male
Moderate: 20-50 oocytes
7
0
4
2
1
Breeding Impacts of the Intersex Condition in Roach
Harris, Hamilton, Runnalls, Jobling, Vinciotti, Henshaw, Hodgson. Coe, Tyler,. Sumpter (2010). EHP. 119:306–311 29
Oocytes
Reproductive Success of Intersex Roach under Competitive Breeding
Intersex Index
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0 1 2 3 4 5
Rep
rod
uctive
su
cce
ss
LME model coefficient = -0.029, p < 0.0001
There was a significant negative correlation between intersex index
and reproductive success.
Harris, Hamilton, et al ( 2010). EHP. 119:306–311 30
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Charles.R.Tyler
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
31
Okhyun Lee, Aya Takensano, Masa Tada, Charles R. Tyler* and Tetsuhiro Kudoh* (2012)- EHP IN
pRess
Green Glowing Transgenic Fish for Understanding the
Wider Health Effects of Environmental Oestrogens
Okhyun Lee, Aya Takensono, Masa Tada, Charles R. Tyler* and Tetsuhiro Kudoh*- EHP. 2012 32
Secondary Response : Gal4ff protein induces synthesis of GFP
Amplification of the signal
Estrogen Receptor
(Xeno-)Estrogen
3ERE
Gal4ffmRNA
UAS
GFPmRNA
GFP protein
Primary Response : Estrogen induces synthesis of Gal4ff protein
2/11/2013
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ERE-Transgenic Zebrafish - Whole body profiling Identifies
Target Tissues for Environmental Oestrogens
The ERE-TG zebrafish are highly sensitive for detecting
exposure to different environmental oestrogens
Control
Okhyun Lee, Aya Takensono, Masa Tada, Charles R. Tyler* and Tetsuhiro Kudoh*- EHP. 2012
Zebrafish provide a model for bridging the gap when discerning
possible health effects of EDCs between wildlife and humans. 33
Key collaborators and sponsors of the work presented:
34
2/11/2013
18
Thank you for listening!
35
Gender Bending Science:
Impacts of Endocrine Disrupting Chemicals
Download the presentation ONE WEEK after webinar:
http://acswebinars.org/gender-bending-chemicals
Contact ACS Webinars™at [email protected]
ACS WEBINARS™ January 31, 2013
Dr. Darren Griffin
University of Kent Dr. Charles Tyler
University of Exeter
36
2/11/2013
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Dr. Thomas M. Zennie
Dr. David Harwell, ACS Careers
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