![Page 1: Risk in innovation: balancing benefits and hazards Case study: endocrine disruption](https://reader035.vdocuments.us/reader035/viewer/2022081512/568166d5550346895ddaeadd/html5/thumbnails/1.jpg)
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
![Page 2: Risk in innovation: balancing benefits and hazards Case study: endocrine disruption](https://reader035.vdocuments.us/reader035/viewer/2022081512/568166d5550346895ddaeadd/html5/thumbnails/2.jpg)
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?
![Page 3: Risk in innovation: balancing benefits and hazards Case study: endocrine disruption](https://reader035.vdocuments.us/reader035/viewer/2022081512/568166d5550346895ddaeadd/html5/thumbnails/3.jpg)
Endocrine disruption is all around us
![Page 4: Risk in innovation: balancing benefits and hazards Case study: endocrine disruption](https://reader035.vdocuments.us/reader035/viewer/2022081512/568166d5550346895ddaeadd/html5/thumbnails/4.jpg)
Eating and drinking causes ‘endocrine disruption’
![Page 5: Risk in innovation: balancing benefits and hazards Case study: endocrine disruption](https://reader035.vdocuments.us/reader035/viewer/2022081512/568166d5550346895ddaeadd/html5/thumbnails/5.jpg)
Diet, hormones and getting fatHormone effects of eating ‘high sugar’ foods
So, is sugar an endocrine disruptor?
![Page 6: Risk in innovation: balancing benefits and hazards Case study: endocrine disruption](https://reader035.vdocuments.us/reader035/viewer/2022081512/568166d5550346895ddaeadd/html5/thumbnails/6.jpg)
Eating and drinking causes ‘endocrine disruption’
Increase in visceral (intra-abdominal) fat leads to a decrease in circulating testosterone levels (even in young men)
![Page 7: Risk in innovation: balancing benefits and hazards Case study: endocrine disruption](https://reader035.vdocuments.us/reader035/viewer/2022081512/568166d5550346895ddaeadd/html5/thumbnails/7.jpg)
Relationship between blood testosterone and metabolic syndrome features in adult men
From: Traish et al (2011) Amer J Med 124: 578-587
![Page 8: Risk in innovation: balancing benefits and hazards Case study: endocrine disruption](https://reader035.vdocuments.us/reader035/viewer/2022081512/568166d5550346895ddaeadd/html5/thumbnails/8.jpg)
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
![Page 9: Risk in innovation: balancing benefits and hazards Case study: endocrine disruption](https://reader035.vdocuments.us/reader035/viewer/2022081512/568166d5550346895ddaeadd/html5/thumbnails/9.jpg)
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
![Page 10: Risk in innovation: balancing benefits and hazards Case study: endocrine disruption](https://reader035.vdocuments.us/reader035/viewer/2022081512/568166d5550346895ddaeadd/html5/thumbnails/10.jpg)
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)
![Page 11: Risk in innovation: balancing benefits and hazards Case study: endocrine disruption](https://reader035.vdocuments.us/reader035/viewer/2022081512/568166d5550346895ddaeadd/html5/thumbnails/11.jpg)
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
![Page 12: Risk in innovation: balancing benefits and hazards Case study: endocrine disruption](https://reader035.vdocuments.us/reader035/viewer/2022081512/568166d5550346895ddaeadd/html5/thumbnails/12.jpg)
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
![Page 13: Risk in innovation: balancing benefits and hazards Case study: endocrine disruption](https://reader035.vdocuments.us/reader035/viewer/2022081512/568166d5550346895ddaeadd/html5/thumbnails/13.jpg)
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
![Page 14: Risk in innovation: balancing benefits and hazards Case study: endocrine disruption](https://reader035.vdocuments.us/reader035/viewer/2022081512/568166d5550346895ddaeadd/html5/thumbnails/14.jpg)
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
![Page 15: Risk in innovation: balancing benefits and hazards Case study: endocrine disruption](https://reader035.vdocuments.us/reader035/viewer/2022081512/568166d5550346895ddaeadd/html5/thumbnails/15.jpg)
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
![Page 16: Risk in innovation: balancing benefits and hazards Case study: endocrine disruption](https://reader035.vdocuments.us/reader035/viewer/2022081512/568166d5550346895ddaeadd/html5/thumbnails/16.jpg)
![Page 17: Risk in innovation: balancing benefits and hazards Case study: endocrine disruption](https://reader035.vdocuments.us/reader035/viewer/2022081512/568166d5550346895ddaeadd/html5/thumbnails/17.jpg)
![Page 18: Risk in innovation: balancing benefits and hazards Case study: endocrine disruption](https://reader035.vdocuments.us/reader035/viewer/2022081512/568166d5550346895ddaeadd/html5/thumbnails/18.jpg)
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
![Page 19: Risk in innovation: balancing benefits and hazards Case study: endocrine disruption](https://reader035.vdocuments.us/reader035/viewer/2022081512/568166d5550346895ddaeadd/html5/thumbnails/19.jpg)
![Page 20: Risk in innovation: balancing benefits and hazards Case study: endocrine disruption](https://reader035.vdocuments.us/reader035/viewer/2022081512/568166d5550346895ddaeadd/html5/thumbnails/20.jpg)
![Page 21: Risk in innovation: balancing benefits and hazards Case study: endocrine disruption](https://reader035.vdocuments.us/reader035/viewer/2022081512/568166d5550346895ddaeadd/html5/thumbnails/21.jpg)
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
![Page 22: Risk in innovation: balancing benefits and hazards Case study: endocrine disruption](https://reader035.vdocuments.us/reader035/viewer/2022081512/568166d5550346895ddaeadd/html5/thumbnails/22.jpg)
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
![Page 23: Risk in innovation: balancing benefits and hazards Case study: endocrine disruption](https://reader035.vdocuments.us/reader035/viewer/2022081512/568166d5550346895ddaeadd/html5/thumbnails/23.jpg)
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’
![Page 24: Risk in innovation: balancing benefits and hazards Case study: endocrine disruption](https://reader035.vdocuments.us/reader035/viewer/2022081512/568166d5550346895ddaeadd/html5/thumbnails/24.jpg)
Effects of perinatal exposure to mixturesof ‘anti-androgenic’ chemicals in rats
Data courtesy of Earl Gray (EPA, USA)
![Page 25: Risk in innovation: balancing benefits and hazards Case study: endocrine disruption](https://reader035.vdocuments.us/reader035/viewer/2022081512/568166d5550346895ddaeadd/html5/thumbnails/25.jpg)
‘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
![Page 26: Risk in innovation: balancing benefits and hazards Case study: endocrine disruption](https://reader035.vdocuments.us/reader035/viewer/2022081512/568166d5550346895ddaeadd/html5/thumbnails/26.jpg)
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
![Page 27: Risk in innovation: balancing benefits and hazards Case study: endocrine disruption](https://reader035.vdocuments.us/reader035/viewer/2022081512/568166d5550346895ddaeadd/html5/thumbnails/27.jpg)
Another case of endocrine disruption?Thank you for your attention