Monograph on the Potential Human Reproductive and ... - OEHHA
Monograph on the Potential Human Reproductive and ... - OEHHA
Monograph on the Potential Human Reproductive and ... - OEHHA
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nTp brief<br />
(96).. In. brief,. estradiol. has. a. clearer. role. in.<br />
regulating. male-typical. brain. <strong>and</strong>. behavioral.<br />
sexual.differentiati<strong>on</strong>.in.rodents.compared.to.<br />
primates.<strong>and</strong>.humans..The.sexual.dimorphism.<br />
of.a.number.of.<strong>the</strong>.neural.<strong>and</strong>.behavioral.endpoints.affected.by.bisphenol.A.exposure,.i.e.,.<br />
AVPV.<strong>and</strong>.LC.volume/cell.number,.locomotor.<br />
activity,.explorati<strong>on</strong>.in.<strong>the</strong>.plus.maze,.have.been.<br />
shown.to.depend.<strong>on</strong>.estradiol.formed.perinatally.in.<strong>the</strong>.male.rodent.brain.via.aromatizati<strong>on</strong>.of.testoster<strong>on</strong>e.secreted.from.<strong>the</strong>.fetal.<strong>and</strong>.<br />
ne<strong>on</strong>atal.testes..To.<strong>the</strong>.extent.that.<strong>the</strong>se.effects.<br />
of.bisphenol.A.are.due.to.its.interacti<strong>on</strong>s.with.<br />
<strong>the</strong>.estrogen.receptor.<strong>the</strong>.translati<strong>on</strong>.of.<strong>the</strong>se.<br />
findings.to.humans.is.not.clear.because.<strong>the</strong>re.<br />
is.currently.no.evidence.that.estrogen.receptor.<br />
signaling.plays.an.essential.role.in.male-typical.<br />
brain.<strong>and</strong>.behavioral.sexual.differentiati<strong>on</strong>.in.<br />
primates.including.humans.(96)..<br />
However,.as.discussed.previously.a.number.of.<br />
studies.suggest.that.bisphenol.A.may.also.exert.<br />
biological. effects. by. mechanisms. that. do. not.<br />
involve.estrogen.receptor.binding..For.this.reas<strong>on</strong>,.<br />
future.neural.<strong>and</strong>.behavioral.studies.of.bisphenol.<br />
A.should.not.focus.exclusively.<strong>on</strong>.estrogen.receptor-mediated.endpoints..For.example,.a.number.of.male-typical.brain.<strong>and</strong>.behavioral.sexual.dimorphisms.in.rodents.depend.<strong>on</strong>.<strong>and</strong>rogen.receptor.signaling,.i.e.,.spinal.nucleus.of.<strong>the</strong>.bulbocavernosus,.<br />
<strong>the</strong>. posterodorsal. medial. amygdalar.<br />
nucleus,.<strong>the</strong>.ventromedial.hypothalamic.nucleus,.<br />
<strong>the</strong>.suprachiasmatic.nucleus,.forebrain.resp<strong>on</strong>se.<br />
to.pherom<strong>on</strong>es,.play.fighting.<strong>and</strong>.<strong>the</strong>.preference.<br />
of.males.to.seek.out.female.vs.same-sex.(male).<br />
urinary.odors..These.<strong>and</strong>rogen.receptor-mediated.<br />
behaviors. are. c<strong>on</strong>sidered. to. have. more. direct.<br />
relevance.to.humans.<strong>and</strong>.should.be.more.thoroughly.assessed.following.bisphenol.A.exposure.<br />
given.suggesti<strong>on</strong>s.that.bisphenol.A.can.modulate.<br />
<strong>and</strong>rogen.receptor.activity.or.expressi<strong>on</strong>.levels.<br />
In.additi<strong>on</strong>,.several.studies.suggest.that.bisphenol.<br />
A.may.interfere.with.<strong>the</strong>.dopaminergic.system..<br />
The.CERHR.Expert.Panel.<strong>on</strong>.Bisphenol.A.did.<br />
21<br />
not. c<strong>on</strong>sider. most. of. <strong>the</strong>se. studies. useful. in.<br />
<strong>the</strong>.evaluati<strong>on</strong>.by.due.to.experimental.design.<br />
limitati<strong>on</strong>s.<strong>and</strong>/or.use.of.a.n<strong>on</strong>-oral.route.of.<br />
administrati<strong>on</strong>..Additi<strong>on</strong>al.research.that.includes.<br />
assessment.of.dopaminergic-related.endpoints.to.<br />
address.<strong>the</strong>.limitati<strong>on</strong>s.in.<strong>the</strong>.current.literature.<br />
would.be.helpful.<br />
Future.studies.should.also.take.precauti<strong>on</strong>s.to.<br />
distinguish.between.“organizati<strong>on</strong>al”.<strong>and</strong>.“activati<strong>on</strong>al”.effects.of.horm<strong>on</strong>es..Organizati<strong>on</strong>al.<br />
effects.are.permanent.<strong>and</strong>.induced.by.horm<strong>on</strong>es.<br />
during.perinatal.life.whereas.activati<strong>on</strong>al.effects.<br />
are. acute,. generally. reversible,. <strong>and</strong>. occur.<br />
throughout.life.(174)..Many.sexual.<strong>and</strong>.o<strong>the</strong>r.<br />
behaviors.reflect.both.organizati<strong>on</strong>al.<strong>and</strong>.activati<strong>on</strong>al.influences.of.horm<strong>on</strong>es.(175)..Observed.<br />
behavioral. effects. of. perinatal. bisphenol. A.<br />
could.reflect.organizati<strong>on</strong>al.changes.in.<strong>the</strong>.brain.<br />
accomplished.during.<strong>the</strong>.normal.perinatal.period.<br />
of.brain.sexual.differentiati<strong>on</strong>.or,.alternatively,.<br />
<strong>the</strong>y.could.simply.reflect.group.differences.in.<br />
plasma.levels.of.circulating.sex.horm<strong>on</strong>es.at.<strong>the</strong>.<br />
time.of.adult.testing..Only.a.small.number.of.<strong>the</strong>.<br />
studies.in.<strong>the</strong>.bisphenol.A.literature.c<strong>on</strong>trolled.<br />
for.<strong>the</strong>.influence.of.differences.in.plasma.levels.<br />
of.circulating.sex.horm<strong>on</strong>es.at.<strong>the</strong>.time.of.testing,.<br />
for.example.by.testing.ovarectomized.females,.<br />
using.females.at.<strong>the</strong>.same.stage.of.<strong>the</strong>.estrouscycle,.or.c<strong>on</strong>ducting.assessments.<strong>on</strong>.pre-pubertal.<br />
animals.(46, 48, 125).<br />
mammary Gl<strong>and</strong><br />
There.is.evidence.from.rodent.studies.suggesting.<br />
that.perinatal.exposure.to.bisphenol.A.via.subcutaneous.mini-pump.at.administered.doses.of.<br />
0.0025.to.1.mg/kg.bw/day.causes.tissue.changes.<br />
(“lesi<strong>on</strong>s”).in.<strong>the</strong>.mammary.gl<strong>and</strong>.that.may.signal.<br />
an.increased.susceptibility.to.develop.mammary.<br />
gl<strong>and</strong>.tumors.later.in.life.(52, 53)..Although.<strong>the</strong>se.<br />
lesi<strong>on</strong>s.have.been.described.as.preneoplastic,.currently.no.data.are.available.that.assess.whe<strong>the</strong>r.<strong>the</strong>.<br />
reported.lesi<strong>on</strong>s.progress.to.invasive.carcinoma..<br />
For.this.reas<strong>on</strong>,.<strong>the</strong>.evidence.is.not.sufficient.to.<br />
c<strong>on</strong>clude.that.bisphenol.A.is.a.rodent.mammary.
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