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greater in males thereby resulting in lower levels of immunoreactivity. That the
density of the ARC kisspeptin-ir fi ber plexus is clearly infl uenced by sex steroids,
resulting in reduced levels in males and estrogen-exposed females, also raises ques-
tions as to their point of origin. If the fi bers arise from the AVPV/PeN population,
then this sex difference in ARC fi ber density is consistent with the sex difference in
neuron number and
Kiss1
expression found in the AVPV/PeN.
Males
Data regarding the vulnerability of the male kisspeptin system to BPA is limited and
confl icting. Subcutaneous injection of 50
g/kg BPA over the fi rst 4 days of life did
not affect kisspeptin-ir fi ber density in either the AVPV/PeN or the ARC of adult
male rats [
96
]. A follow-up study by the same group employing a similar exposure
paradigm but with an additional dose (50
μ
g/kg or 50 mg/kg BPA) found that on
postnatal day (PND) 10, when
Kiss1
expression is just beginning to become appar-
ent in the AVPV/PeN, expression was unaltered by BPA compared to unexposed
control males [
103
]. In contrast, females exposed to either dose had fewer
Kiss1 -
expressing neurons compared to unexposed females. ARC
Kiss1
levels were
unchanged in either sex on PND 4 or 10.
Exposure spanning a longer duration or encompassing a different developmental
critical period may be required to modify male kisspeptin signaling pathways [
104
].
Males exposed to 2
μ
g/kg BPA from the tenth day of gestation through the fi rst week
after birth by injection to the dam had signifi cantly more AVPV/PeN kisspeptin
perikarya than unexposed males in peripuberty and adulthood. Moreover, these
males displayed an E2-induced LH surge comparable in magnitude to females, indi-
cating that BPA inhibited the defeminization of the neuroendocrine circuitry required
to mediate steroid positive feedback. This was accompanied by a signifi cant reduc-
tion in GnRH neuron numbers, an observation which is diffi cult to reconcile in light
of the other data. An important caveat of this study is that the axonal transport
blocker colchicine was administered prior to sacrifi ce to enhance visualization of
kisspeptin soma, which is not readily immunolabeled in the rat. Although colchicine
is often used for this technical purpose, it can also alter the synthesis of the com-
pound of interest [
105
], making it a potential confounder for a toxicological study.
Emerging evidence indicates that
Kiss1
expression in the male MeA is also vul-
nerable to BPA exposure. In rats, exposure to low levels of BPA through drinking
water across gestation and lactation (via the dam) and peripuberty (via direct con-
sumption) abrogates
Kiss1
expression in the pubertal male MeA, but not the female
MeA. Decreased MeA
Kiss1
expression was accompanied by higher levels of anxi-
ety and the downregulation of other genes associated with sociosexual behavior
including ER
μ
(Patisaul et al., in review). The downregulation of
Kiss1
by BPA was
recapitulated by Ethinyl estradiol (EE) exposure, suggesting it is an estrogenic
effect, an outcome which is unusual because estrogen typically masculinizes, rather
than demasculinizes the rodent brain. Importantly, serum BPA levels in this study
β
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