Endocrine Disruptors and Hormonal Cancer

7/25/2019 Endocrine Disruptors and Hormonal Cancer

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Endocrine disruptors and

hormonal cancer (testis, ovary,prostate, uterus, mammary

gland)

Stan Cornelia Paula

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Cluj-Napoca

2016

1. Endocrine disruptors

Endocrine disruptors are chemicals that, at certain doses, can interfere with endocrine(orhormone s!stems" #hese disruptions can cause cancerous tumors, $irth defects, and other

de%elopmental disorders"&n! s!stem in the $od! controlled $! hormones can $e derailed $!

hormone disruptors" Specificall!, endocrine disruptors ma! $e associated with the de%elopment

of learnin' disa$ilities, se%ere attention deficit disorder, co'niti%eand $rain de%elopment

pro$lems, deformations of the $od! (includin' lim$s, $reast cancer, prostate cancer, th!roid and

other cancers, seual de%elopment pro$lems such as femini)in' of males or masculini)in' effects

on females, etc"

*ound in man! household and industrial products, endocrine disruptors are su$stances

that +interfere with the s!nthesis, secretion, transport, $indin', action, or elimination of naturalhormones in the $od! that are responsi$le for de%elopment, $eha%ior, fertilit!, and maintenance

of homeostasis (normal cell meta$olism"+ #he! are sometimes also referred to as hormonall!

acti%e a'ents, endocrine disruptin' chemicals or endocrine disruptin' compounds"

#he Endocrine Societ! released a statement on Endocrine-isruptin' Chemicals (ECs

specificall! listin' these $iolo'ical aspects as $ein' affected if eposed to ECs"

.$esit!

ia$etes

*emale reproduction

/ale reproduction

ormone-sensiti%e cancers in females

Prostate cancer in males

#h!roid

Neurode%elopment and neuroendocrine s!stems

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#he critical period of de%elopment for most or'anisms is $etween the transition from a

fertili)ed e'' into a full! formed infant" &s the cells $e'in to 'row and differentiate, there are

critical $alances of hormones and protein chan'es that must occur" #herefore, a dose of

disruptin' chemicals ma! do su$stantial dama'e to a de%elopin' fetus" #he same dose ma! not

si'nificantl! affect adult mothers"

Studies in cells and la$orator! animals ha%e shown that ECs can cause

ad%erse $iolo'ical effects in animals, and low-le%el eposures ma! also cause similar effects in

human $ein's"

2. How do endocrine disruptors work?

*rom animal studies, researchers ha%e learned much a$out the mechanisms throu'hwhich endocrine disruptors influence the endocrine s!stem and alter hormonal functions"

Endocrine disruptors can

/imic or partl! mimic naturall! occurrin' hormones in the $od! lie estro'ens (the

female se hormone, andro'ens (the male se hormone, and th!roid hormones, potentiall!

producin' o%erstimulation"

ind to a receptor within a cell and $loc the endo'enous hormone from $indin'" #he

normal si'nal then fails to occur and the $od! fails to respond properl!" Eamples of

chemicals that $loc or anta'oni)e hormones are anti-estro'ens and anti-andro'ens"

3nterfere or $loc the wa! natural hormones or their receptors are made or controlled, for

eample, $! alterin' their meta$olism in the li%er"

3. ynthetic Endocrine !isruptors

!iethylstil"estrol (!E)is considered an EC $ecause it was

released into the en%ironment while $ein' used to accelerate wei'ht 'ain in cattle and poultr!"

ES is the $est nown E with stron' estro'enic acti%it!" 3t was first s!nthesi)ed in 145 and

has since $een widel! used worldwide for medical )indications includin' pre'nanc! toemia and

preterm la$or" owe%er, an increase in $reast cancer incidence was o$ser%ed in mothers eposed

to ES" 3t was also shown that the incidence of cer%ical cancer, o%arian 'erm cell cancer,

cer%ical or %a'inal d!splasia, and %a'inal clear-cell adenocarcinoma was increased in female

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infants $orn to mothers eposed to ES" #he production or maretin' of this chemical is

prohi$ited since 1447"

Eperiments in mice re%ealed that prenatal and neonatal ES $loced stromal induction

of stratification of the %a'inal epithelium, and resulted in the de%elopment of simple columnar

epithelium, which is normall! present in the uterus" /ost of the %a'inal epithelium, howe%er,

$ecomes stratified upon discontinuation of dieth!lstil$estrol eposure, $ut islands of non-

induced epithelium end up de%elopin' 'lands similar to those found in the endometrium which

persist throu'hout adult life" #hese ectopic 'lands are $elie%ed to $e the tissue where clear cell

carcinoma of the %a'ina ori'inates (8urita et al" 2009"

/c:achlan et al" (140 demonstrated that prenatal ES eposure in mice resulted in

neoplasias of the uterus and 'enital tract a$normalities" & hi'h incidence of uterine

adenocarcinomas (New$old et al" 1440 and male reproducti%e tract tumors could also $e

produced after acute neonatal eposure to ES" Studies su''est that the carcino'enic effects of

ES ma! $e transmitted to succeedin' 'enerations (New$old et al 2000;


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sin'le oral dose of #C, crossfostered the animals to eliminate lactation eposure, and treated

the pups at seual maturit! with /&" #he prenatal #C treatment led to twice as man!

mammar! tumors se%eral months later" #his raises the @uestion of how prenatal #C increases

the sensiti%it! of the pups to /&-induced mammar! cancer" rown and co-worers did not

o$ser%e an! effects on estrus c!clicit! or an! e%idence of clear estro'enicit! of the dioin

treatment, $ut did note an increased num$er of terminal end $ud structures at the time of /&

eposure, su''estin' that #C dela!ed 'land maturation"

#he 's (poly"rominated "iphenyls), possessin' multiple endocrine

modulator! effects includin' estro'enic pertur$ation, are associated with an increase in li%er

tumors in $oth rats and mice after prenatal eposure (Chha$ra et al" 1445$" #he! $elon' to a

class of toic chemicals nown as pol!halo'enated aromatic h!drocar$ons (P&s, which

includes the pol!halo'enated di$en)o-p dioins, di$en)ofurans, $iphen!ls, and naphthalenes"

#he mem$ers can $e chlorinated, $rominated, or ha%e mied chloro-$romo su$stitution" #he

P&s pro%ide the $est eamples of persistent ECs in the en%ironmental settin'"/ultiple eamples of endocrine disruption caused $! mem$ers of this class ha%e $een

o$ser%ed in wildlife (fish, $irds, and mammals and domestic animals (cows, sheep, horses,

chicens, as well as in a host of la$orator! animals, with representati%es from all %erte$rate

classes includin' nonhuman primates (irn$aum :"S" 2000" *or eample, the disruption of

reproduction in trout of the Areat :aes in the Bnited States has $een associated with eposure

to dioin (B"S" EP& 1445, and the lac of reproduction of wild min has $een attri$uted to

en%ironmentall! rele%ant dietar! le%els of pol!chlorinated $iphen!ls (PCs (runstrom et al"

2001"

#he enoestro'en isphenol ( ')is one of the ECs that has $een mostthorou'hl! studied" Pa is found in %arious consumer products includin' $a$! $ottles, reusa$le

water $ottles and reusa$le food containers, pol!%in!l chloride stretch films, papers, card$oards

and in the epo! resins linin' the insides of food cans"

>ats eposed prenatall! to en%ironmentall! rele%ant doses of P& show an increased

num$er of intraductal h!perplasias (precancerous lesions that appear durin' adulthood while

hi'h doses induce the de%elopment of carcinomas in situ(urando et al 2007.&nimals eposed

durin' fetal life to P& de%elop palpa$le tumors durin' earl! adulthood when treated at =0 da!s

of a'e with nitrosometh! urea, a chemical carcino'en" Eposure to P& durin' nursin' followed

$! eposure at =0 da!s of a'e to dimeth!l$en)antracene resulted in an increased num$er of

tumors per rat and a decreased latenc! period compared with animals not eposed to P& durin'

nursin'" >e'ardless of the rat strain, eposure routes and le%els, and timin's of eposure to P&,

all studies show an increased suscepti$ilit! to mammar! 'land neoplasia that manifests durin'

adulthood (/urra! et al" 2007"

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&t pu$ert!, an increased sensiti%it! to estradiol was o$ser%ed in the mammar! 'lands of

animals eposed fatall! to P&, which led to the induction of pro'esterone receptors in epithelial

cells and to increased duct lateral $ranchin' (/uo)-de-#oro et al" 200="

&s a side-note, neoplasias that result from eposures to P& and ES durin'

em$r!o'enesis and or'ano'enesis usuall! appear after seual maturit! is complete"

!io$insare $!products of com$ustion and of multiple industrial processes" #he! ha%e

$een identified as a class 1 carcino'en $! the 3nternational &'enc! for >esearch on Cancer and

ha%e also $een identified as reproducti%e and endocrine toicants (Steenland et al" 2009"

#he protot!pe chemical for this class is dioin, or 2,3,*,+

tetrachlorodi"en-opdio$in (#!!)" .ften called the most toic man-made

compound, dioin can cause a host of effects" &lthou'h essentiall! all %erte$rates are sensiti%e to

its effects, not e%er! effect ma! occur in all species" 3n addition, man! of the responses are

de%elopmental sta'e- or se-dependent"

3n cell culture studies, #C, $! $indin' to the ar!l h!drocar$on receptor, interacts withestro'en receptors, and thus $eha%es either as an estro'en a'onist or anta'onist" *urthermore, in

mice, #C $locs estro'en-induced responses in se%eral tissues (*enton et al" 2002" #Ceposure durin' or'ano'enesis alters mammar! 'land morpho'enesis as e%aluated $! the

persistence of terminal end $uds in eposed rats (rown et al"144" #hese transient structures

are considered the loci where cancer forms" eposure of these rats to the carcino'endimeth!l$en)antracene at pu$ert! increases their tumor incidence and shortens the latenc! period

as compared to animals not eposed to #C"

/ale rodents eposed to 2,5,7,-tetrachlorodi$en)o-p-dioin (#C in intrauterine life

were found to eperience pro$lems in masculini)ation of internal and eternal 'enitalia, descent

of testicles, andro'en production and in spermato'enesis"

onclusions

3n conclusion, it is worth notin' that for Es, to cause impairment of endocrine

functions, time of eposure is as important as dose, duration and a'e at eposure" /oreo%er, a

sin'le chemical su$stance ma! result in multiple endocrine s!stem d!sfunctions %ia se%eral

mechanisms" & s!stems $iolo'! approach should $e adopted to tacle this compleit! due to the

fact that endocrine disruptin' chemicals act additi%el!Dtheir multiple and comple effects are

dose-dependent and contetual

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i"liography

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mouse genital tract associated with prenatal exposure to diethylstilbestrol " Cancer

>es 9054?5444"

2" New$old >>, ulloc , /c:achlan &" 1440. Uterine adenocarcinomas in mice

following developmental treatment with estrogens: a model for hormonal

carcinogenesis.Cancer >es 907677?761"

5" New$old >>, anson >, efferson


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10" irn$aum :S" 2000. +ealth effects of dioxins: people are animals, and vice-versa

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Reproductive toxicity in min /Mustela vison0 chronically exposed to

environmentally relevant polychlorinated biphenyl concentrations.En%iron #oicol

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*nduction of mammary gland ductal hyperplasias and carcinoma in situ following

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peripubertal mammary gland development in mice.Endocrinology 196, 915?9197"

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developments since the 122& i(R) classification of dioxin as a human carcinogen.

Environ. Health Perspect. 112, 126=?126 "16" *enton, S" E", amm, " #", irn$aum, :" F Goun'$lood, A" :"2002" Persistent

abnormalities in the rat mammary gland following gestational and lactational

exposure to 3,!,&,4- tetrachlorodiben5o-p-dioxin /')##0.Toxicol. ci. 67, 65?79

17.rown, N" /", /an)olillo, P" &", Hhan', " I", wan', " F :amartiniere, C" &" 144"

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Endocrine Disruptors and Hormonal Cancer