Risk in innovation: balancing benefits and hazards
Case study: endocrine disruption
Richard M SharpeE-mail: [email protected]
The Queen’s Medical Research Institute Medical School Main Hospital
Endocrine disruption and human healthAn 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 fatHormone 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 disruptorsDefinition – 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
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
A
Other compounds have activities that alter endogenous hormone production within the body. Examples are certain phthalates, azole compounds, bisphenol A
B
The commonest reproductive disorders of the developing and young adult male‘Testicular dysgenesis syndrome (TDS)’
CryptorchidismHypospadias
Testis GC cancerLow sperm countsLow testosterone
? Subnormal
T productionor 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
Partly from Scott et al (2008) Endocrinology 149:5820
Control
DBP
Fetal human testis xenograftinginto (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
From Mitchell et al (2012) JCEM 97: E341-E348
Data show Means ± SEM for N=8 fetuses (14-20 weeks’ gestation)Statistical analysis was by paired t test
Xenografts recovered + 6 weeks; hCG treatment from 1-6 weeks
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 estrogenicityThe 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 dietfor 3 days on Bisphenol A exposure
From: Rudel et al (2011) Environ Health Perspect 119: 914
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
This is what we suggest as a hypothesis – which requires urgent investigation
RM Sharpe & AJ Drake
Western diet
Obesity, type 2 diabetes etc
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 mixturesof ‘anti-androgenic’ chemicals in rats
Data courtesy of Earl Gray (EPA, USA)
‘Real-world’ exposure to environmentalchemicals: effects on testis development
Ewes reared on pasture fertilized with:
• Conventional fertiliser (= control)
• Sewage sludge* (= treated)
*According to EU recommendations
For ~20 common contaminantsquantified in mothers/fetuses
there was no significant increase in sludge-exposed animals
Adapted from Bellingham et al (2011) Int J Androl doi: 10.1111/j.1365-2605.2011.01234.x
Sperm production in adulthood in sheepafter rearing on control or ‘treated’ pasture
Another case of endocrine disruption?Thank you for your attention
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