Risk in innovation: balancing benefits and hazards Case study: endocrine disruption

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Risk in innovation: balancing benefits and hazards Case study: endocrine disruption. The Queen’s Medical Research Institute Medical School Main Hospital. Richard M Sharpe E-mail: r.sharpe@ed.ac.uk. Endocrine disruption and human health An up-front reality check. - PowerPoint PPT Presentation

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How to make a male: Fetal origins of the common male reproductive disorders

Risk in innovation: balancing benefits and hazardsCase study: endocrine disruption

Richard M SharpeE-mail: r.sharpe@ed.ac.uk

The Queens Medical Research Institute Medical School Main HospitalIf time is an issue, slides 5, 6, 7 would be a group I would consider cutting.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 diseasesTherefore, identifying the causes and preventing them is both desirable and feasibleThe 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 foodsSo, 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 menFrom: Traish et al (2011) Amer J Med 124: 578-587

Endocrine disruptorsDefinition why the concernEndocrine 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)populationsMany 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

AOther 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 maleTesticular dysgenesis syndrome (TDS) CryptorchidismHypospadiasTestis GC cancerLow sperm countsLow testosterone? SubnormalT productionor actionAn 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: CryptorchidismHypospadiasLow testis weight/subfertilityAbnormalities in fetal germ cell developmentSuppression of fetal testosterone and Insl3Reduction 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 149:5820ControlDBPFetal 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 graftsExposure of human fetal testis xenografts to 500mg/kg/day DBP has no steroidogenic effectsFrom 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 testXenografts recovered + 6 weeks; hCG treatment from 1-6 weeksThe (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 activityBisphenol 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 exposedOur main route (95%) of exposure is dietary (oral)Conjugation of BPA occurs rapidly in the body rendering it biologically inactiveMost 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: 914So 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 etcThis is what we suggest as a hypothesis which requires urgent investigation

RM Sharpe & AJ DrakeWestern dietObesity, type 2 diabetes etcHigher bisphenol A exposureA real endocrine disruptor issue that will not go awayThe risk posed by exposure to low level combinations of endocrine disruptors

The mixtures issue - The cocktail effectEffects 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 recommendationsFor ~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 pastureAnother case of endocrine disruption?Thank you for your attention