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 />
to.be.quantified.in.<strong>the</strong>.blood.of.adults..However,.<br />
in.4-.day.old.male.<strong>and</strong>.female.rats.treated.with.1.<br />
mg/kg.of.bisphenol.A,.98.–.100%.of.administered.<br />
bisphenol.A.was.detected.as.bisphenol.A-glucur<strong>on</strong>ide<br />
8 .compared.to.71.–.82%.at.10.mg/kg,.i.e.,.<br />
a.smaller.proporti<strong>on</strong>.of.administered.bisphenol.<br />
A.is.glucur<strong>on</strong>idated.at.10.mg/kg.compared.to.1.<br />
mg/kg..This.would.be.expected.when.<strong>the</strong>.limited.capacity.of.young.animals.to.metabolize.bisphenol.A.is.overwhelmed.by.higher.dose.levels.of.<strong>the</strong>.compound..These.data.suggest.more.<br />
efficient.metabolism.by.ne<strong>on</strong>atal.rats.at.1.mg/kg.<br />
compared.to.10.mg/kg.<strong>and</strong>.imply.that.<strong>the</strong>.age.<br />
at.exposure.differences.described.above.may.<br />
be.less.profound.in.<strong>the</strong>.“low”.dose.range.(≤.5.<br />
mg/kg.bw/day).<br />
Taken.toge<strong>the</strong>r.<strong>the</strong>se.data.indicate.that,.compared.to.adults.at.a.given.dose,.ne<strong>on</strong>atal.rats.(<strong>and</strong>.<br />
presumably.mice).metabolize.bisphenol.A.more.<br />
slowly.<strong>and</strong>.suggest.that.differences.in.circulating.levels.of.free.bisphenol.A.arising.from.oral.<br />
<strong>and</strong>.subcutaneous.routes.of.administrati<strong>on</strong>.as.a.<br />
result.of.“first-pass.metabolism”.are.reduced.in.<br />
fetal.or.infant.animals.compared.to.adults..This.<br />
predicti<strong>on</strong>.is.supported.by.a.recent.study.that.did.<br />
not.detect.differences.in.<strong>the</strong>.blood.c<strong>on</strong>centrati<strong>on</strong>.of.free.bisphenol.A.as.a.functi<strong>on</strong>.of.route.<br />
of. administrati<strong>on</strong>. (oral. versus. subcutaneous.<br />
injecti<strong>on</strong>).in.3-.day.old.female.mice.following.<br />
treatment.with.ei<strong>the</strong>r.0.035.or.0.395.mg/kg.of.<br />
bisphenol.A.(92).<br />
Additi<strong>on</strong>al.research.is.needed.to.underst<strong>and</strong>.<strong>the</strong>.<br />
metabolism.of.bisphenol.A.in.both.laboratory.<br />
animals.<strong>and</strong>.humans..For.example,.a.complete.<br />
assessment.of.<strong>the</strong>.UDP-glucur<strong>on</strong>osyltransferase.<br />
(UGT). <strong>and</strong>. sulfotransferase. (SULT). isoforms.<br />
involved. in. <strong>the</strong>. glucur<strong>on</strong>idati<strong>on</strong>. <strong>and</strong>. sulfati<strong>on</strong>.<br />
of.bisphenol.A.is.needed.for.both.rodents.<strong>and</strong>.<br />
humans..UGT2B1.has.been.identified.as.<strong>the</strong>.prin-<br />
8 Based.<strong>on</strong>.percentage.of.plasma.area.under.<strong>the</strong>.<br />
curve.(AUC).for.radioactivity.that.was.bisphenol.<br />
A.glucur<strong>on</strong>ide.<br />
13<br />
ciple.UGT.isoform.that.metabolizes.bisphenol.A.<br />
to.bisphenol.A.glucur<strong>on</strong>ide.in.<strong>the</strong>.rat.(20)..This.<br />
isoform.shows.low.expressi<strong>on</strong>.<strong>and</strong>.activity.during.development..However,.it.is.important.to.note.<br />
that.<strong>the</strong>.Matsumoto.et al..study.<strong>on</strong>ly.characterized.UGT2B1.activity.during.development.<strong>and</strong>.<br />
did.not.include.o<strong>the</strong>r.members.of.<strong>the</strong>.UGT2B.<br />
family..Thus,. <strong>the</strong>. underst<strong>and</strong>ing. of. bisphenol.<br />
A. metabolism. during. development. in. <strong>the</strong>. rat.<br />
is.still.incomplete..In.additi<strong>on</strong>,.it.is.difficult.to.<br />
translate.<strong>the</strong>.rat.findings.to.humans.because.<strong>the</strong>.<br />
UGT.isoform(s).that.metabolize.bisphenol.A.in.<br />
humans.have.not.been.identified..<strong>Human</strong>s.have.7.<br />
members.of.<strong>the</strong>.UGT2.family.that.have.functi<strong>on</strong>al.<br />
activity,.1.UGT2A.<strong>and</strong>.6.UGT2B.isoforms..<br />
In.c<strong>on</strong>trast,.<strong>the</strong>re.is.informati<strong>on</strong>.<strong>on</strong>.<strong>the</strong>.SULT.<br />
isoforms.that.metabolize.bisphenol.A.in.humans..<br />
In.humans,.SULT1A1.has.been.identified.as.<strong>the</strong>.<br />
SULT.with.<strong>the</strong>.highest.catalytic.activity.towards.<br />
bisphenol.A,. although. SULT1E1,. SULT2A1.<br />
<strong>and</strong>. a. SULT1C. isoforms. are. also. capable. of.<br />
catalyzing.bisphenol.A-sulfate.formati<strong>on</strong>.(21)..<br />
In.humans,.SULT1A1.activity.is.comparable.<br />
in.fetal.<strong>and</strong>.postnatal.liver.although.<strong>the</strong>re.are.<br />
differences.in.localizati<strong>on</strong>.(hematopoietic.stem.<br />
cells. during. fetal. life. <strong>and</strong>. hepatocytes. after.<br />
birth)..Characterizing.<strong>the</strong>.<strong>on</strong>togeny.of.individual.<br />
UGT.<strong>and</strong>.SULT.enzymes.is.complex.as.specific.<br />
isoforms.show.unique.patterns.of.expressi<strong>on</strong>.<br />
during.development.<strong>and</strong>.also.vary.with.respect.<br />
to.preferred.substrates.<strong>and</strong>.associated.catalytic.<br />
activity..As.a.result,.it.is.unknown.if.<strong>the</strong>.various.metabolic.pathways.provide.for.“sufficient”.<br />
metabolism. of. low. doses. of. bisphenol.A. in.<br />
humans.exposed.during.fetal.life.<strong>and</strong>.infancy..<br />
Although.infants.can.metabolize.bisphenol.A,.it.<br />
is.likely.that.significant.variati<strong>on</strong>.in.<strong>the</strong>.developmental.profile,.e.g.,.rate.<strong>and</strong>.extent.of.metabolic.<br />
capacity,.would.be.observed.at.<strong>the</strong>.populati<strong>on</strong>.<br />
level..The.issue.of.sulfati<strong>on</strong>.is.also.important.<br />
given.<strong>the</strong>.role.of.sulfati<strong>on</strong>.pathways.in.regulating.endogenous.compounds.that.are.involved.in.<br />
c<strong>on</strong>trolling.<strong>the</strong>.growth.<strong>and</strong>.functi<strong>on</strong>.of.some.of.<br />
<strong>the</strong>.reproductive.tissues.identified.as.targets.of.
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