Monograph on the Potential Human Reproductive and ... - OEHHA

of.normal.sex-based.differences.between.males.
and.females.(“sexual.dimorphisms”.or.“sexually.
dimorphic”)..
Research.on.the.effects.of.bisphenol.A.on.the.
brain.and.behavior.does.not.have.as.long.a.history.as.the.assessment.of.reproductive.tissues,.
but.is.now.an.active.area.of.study.that.has.been.
growing. quickly. in. the. past. few. years.. Currently,.the.literature.is.composed.of.a.collection.
of.findings.based.on.behavioral.assessments,.
morphometric.and.cell-based.measurements.of.
the. brain. of. laboratory. animals,. and. in vitro
studies.to.identify.molecular.and.cellular.targets.
and.mechanisms.of.action..From.these.studies,.
themes.are.emerging.that.suggest.exposures.to.
bisphenol.A.can.produce.a.loss.or.reduction.of.
sexual.dimorphisms.in.non-reproductive.behaviors.and.in.certain.regions.of.the.brain.as.well.
as.effects.on.the.dopaminergic.system..Neural.
effects. are. also. implicated. from. mechanistic.
studies.that.show.bisphenol.A.can.interfere.with.
thyroid.hormone.signaling..
Sexual.dimorphisms.include.differences.in.the.
size,.cellular.composition,.or.molecular.expression.patterns.of.specific.regions.or.structures.
in.the.brain..The.studies.detecting.bisphenol.
A-induced.changes.in.sexually.dimorphic.brain.
structures.generally.report.a.reduction.or.loss.of.
sexual.dimorphisms,.for.example,.in.the.locus.
ceruleus.(LC;.a.brain.region.involved.in.mediating.responses.to.stress).(121,
122),.and.the.
bed.nucleus.of.the.stria.terminalis.(involved.in.
regulating.emotional.behavior).(123)..Similar.
effects.are.reported.in.some,.but.not.all,.studies.
(124 – 126).of.the.anteroventral.periventricular.
nucleus.(AVPV),.a.brain.region.that.provides.
input.to.gonadotropin-releasing.hormone.neurons.involved.in.regulating.ovulation..The.lowest.
administered.doses.delivered.to.either.pregnant.
dams.or.neonatal.animals.associated.with.these.
effects.range.from.~0.03.mg/kg.bw/day.(oral).
(122),. 0.000025. mg/kg. bw/day. (subcutaneous.mini-pump).(125)
to.~100.mg/kg.bw/day.
18
(subcutaneous.injection).(124)..Changes.are.not.
reported.for.all.sexually.dimorphic.structures..
One.well-known.sexually.dimorphic.structure.
reportedly.not.affected.even.at.doses.up.to.320.
mg/kg.bw/day.in.rats.is.the.sexually.dimorphic.
nucleus.in.the.preoptic.area.(SDN-POA),.a.brain.
region.that.has.a.homologue.in.humans.and.is.
known. to. be. modified. by. gonadal. hormones.
during.perinatal.life.(116, 118, 121, 122, 126,
127)..Interpreting.the.potential.human.health.or.
behavioral.significance.of.effects.on.sexually.
dimorphic.brain.regions.can.be.difficult..For.
example,.the.bed.nucleus.of.the.stria.terminalis.
is.described.as.being.responsive.to.reproductive.
hormones.and.generally.involved.in.regulating.
emotional.behavior.(128),.but.the.specific.functions.of.this.brain.region.in.rats,.and.therefore.
the.impact.of.loss.of.sexual.dimorphism,.remain.
unclear..
Effects.on.behavior.have.been.assessed.by.a.
wide. variety. of. experimental. tests.. Reported.
behavioral.changes.in.rats.or.mice.relate.to.play.
(129),.maternal.behavior.(44, 112),.aggression.
(130, 131),.cognitive.function.(132),.motor.activity.(133,
134),.exploration.(46),.novelty-seeking.
(45, 46,135),.impulsivity.(135),.reward.response.
(45, 135 – 137),.pain.response.(138),.anxiety.and.
fear.(46, 48, 50, 139),.and.social.interactions.
(140)..Many.of.these.behaviors,.including.activity,.anxiety,.exploration,.and.novelty.seeking.are.
sexually.dimorphic.to.some.degree..The.lowest.
oral.dose.associated.with.behavioral.changes.is.
0.01.mg/kg.bw/day.(via.treatment.to.the.pregnant.dam).(44
– 46).and.a.number.of.behavioral.
changes.have.been.reported.following.developmental.exposure.to.oral.doses.between.0.01.and.
1.mg/kg.bw/day.(48, 50, 112, 129 – 132, 135,
138, 140 – 142)..
With.the.exception.of.a.study.that.showed.a.
slight.increase.in.receptive.behavior.in.females.
and. an. impairment. of. sexual. performance.
in.males.(130),.the.loss.of.behavioral.sexual.
dimorphisms. does. not. relate. to. reproductive.
nTp brief