The Queen’s Medical Research Institute
Medical School
Main Hospital
Risk in innovation:
balancing benefits and hazards
Case study: endocrine disruption
Richard M Sharpe
E-mail: r.sharpe@ed.ac.uk
Endocrine disruption and human health
An up-front reality check
Endocrine disruption is responsible for a major portion
of human health disorders and is certainly responsible
for the changing face of human disease – so-called
‘Western diseases’
Therefore, identifying the causes and preventing
them is both desirable and feasible
The big issue is what is causing the endocrine
disruption?
Is it environmental ‘endocrine disruptors’ or is it other
factors related to our modern lifestyle?
Endocrine disruption is all around us
Eating and drinking causes ‘endocrine disruption’
Diet, hormones and getting fat
Hormone effects of eating ‘high sugar’ foods
So, is sugar an endocrine disruptor?
Eating and drinking causes ‘endocrine disruption’
Increase in visceral (intra-abdominal)
fat leads to a decrease in circulating
testosterone levels (even in young
men)
Relationship between blood testosterone
and metabolic syndrome features in adult men
From: Traish et al (2011) Amer J Med 124: 578-587
Endocrine disruptors
Definition – why the concern
Endocrine disruptors are exogenous substances that
alter function(s) of the endocrine system and
consequently cause adverse health effects in an intact
organism, or its progeny, or (sub)populations
A
Many man-made chemicals have intrinsic agonistic or antagonistic
hormonal activity and may thus affect one or more hormone
systems in the body. Examples are: alklyphenols, DDT, certain other
pesticides, bisphenol A
B
Other compounds have activities that alter endogenous hormone
production within the body. Examples are certain phthalates, azole
compounds, bisphenol A
The commonest reproductive disorders of
the developing and young adult male
‘Testicular dysgenesis syndrome (TDS)’ Testis GC cancer
Low sperm counts
Low testosterone
Cryptorchidism
Hypospadias
?
Subnormal
T production
or action
An animal model for human TDS?
•Gestational exposure (E13-E21) of the rat to high
doses of certain phthalate esters [eg dibutyl phthalate
(DBP) or diethylhexyl phthalate] results in:
Dose-dependent induction of:
•Cryptorchidism
•Hypospadias
•Low testis weight/subfertility
•Abnormalities in fetal germ cell development
•Suppression of fetal testosterone and Insl3
•Reduction in anogenital distance (AGD)
Exposure of pregnant rats to a plasticiser (dibutyl
phthalate (DBP; 500mg/kg/day) reduces fetal testosterone
Control
DBP
Partly from Scott et al (2008) Endocrinology 149:5820
Fetal human testis xenografting
into (castrate male) nude mice
• Grafts grow normally for 6+
weeks
• Treating the host with DBP is
thus like experimentally
exposing the real human fetal
testis
• Can measure testosterone
production by the grafts
Exposure of human fetal testis xenografts to
500mg/kg/day DBP has no steroidogenic effects
Xenografts recovered + 6 weeks; hCG treatment from 1-6 weeks
Data show Means ± SEM for N=8 fetuses (14-20 weeks’ gestation)
Statistical analysis was by paired t test
From Mitchell et al (2012) JCEM 97: E341-E348
The (ongoing) bisphenol A story
‘Feeding your baby
from a
polycarbonate milk
bottle* is like
feeding it a
contraceptive pill’
(Fred vom Saal)
*containing bisphenol A,
which has weak estrogenic activity
Bisphenol A estrogenicity
The reality
The reality is that you would
need thousands of ‘bisphenol A
pills’ to match an oral
contraceptive pill for estrogenic
potency
So what is the ‘truth’ about bisphenol A?
Is it an ‘obesogen’?
•We are all exposed
•Our main route (95%) of exposure is dietary
(oral)
•Conjugation of BPA occurs rapidly in the body
rendering it biologically inactive
•Most measurements of BPA in the body
(including exposure) are detecting primarily
conjugated BPA
Effect of switching to a fresh food diet
for 3 days on Bisphenol A exposure
So a ‘healthier’ fresh food
diet is associated with
markedly lower BPA levels.
Such a diet is also clearly
associated with lower risk
of obesity, type 2 diabetes,
cardiovascular disease etc
From: Rudel et al (2011) Environ Health Perspect 119: 914
This is what we suggest as a hypothesis –
which requires urgent investigation
RM Sharpe & AJ Drake
Obesity, type 2 diabetes etc
Western diet
Higher bisphenol A exposure
A real endocrine disruptor issue that
will not go away
The risk posed by exposure to ‘low level’
combinations of endocrine disruptors
The ‘mixtures’ issue - ‘The cocktail effect’
Effects of perinatal exposure to mixtures
of ‘anti-androgenic’ chemicals in rats
Data courtesy of Earl Gray (EPA, USA)
‘Real-world’ exposure to environmental
chemicals: effects on testis development
Ewes reared on pasture fertilized with:
•Conventional fertiliser (= control)
•Sewage sludge* (= treated)
For ~20 common contaminants
quantified in mothers/fetuses
there was no significant increase
in sludge-exposed animals
*According to EU recommendations
Sperm production in adulthood in sheep
after rearing on control or ‘treated’ pasture
Adapted from Bellingham et al (2011) Int J Androl doi: 10.1111/j.1365-2605.2011.01234.x
Another case of endocrine disruption?
Thank you for your attention