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were within the range reported for humans (Table
21.1
; [
43
]), suggesting that the
results may have human relevance. These data provide the fi rst indication of what
the functional role of this Kp population might be and the fi rst piece of evidence that
they are sensitive to low levels of environmental estrogens.
Overall, there is sparse but clear evidence of BPA effects on the ontogeny and
function of kisspeptin signaling pathways in both sexes (Table
21.2
). What
remains to be determined is if effects occur at levels considered relevant to humans
and in species other than rodents. Human plasma BPA levels are generally in the
range of 2-4 ng/mL [
43
] and exposure is primarily oral, so this route of adminis-
tration is considered more relevant when assessing the potential for human risk. It
will also be important to explore effects in non-rodent species because, as dis-
cussed at length in the preceding chapters, there are substantive species differ-
ences in the location and function of kisspeptin neurons, most notably in the
preoptic region [
106
].
PCB Effects on the Rodent Kisspeptin System
Females
In rodents, perinatal PCB exposure induces a suite of reproductive effects compa-
rable to BPA. Human relevant exposure levels have sex-dependent effects on
reproductive physiology, hypothalamic sexual differentiation, and neuroendocrine
gene and protein expression in adulthood [
107
,
108
]. Two studies, both conducted
by the same group, have shown that PCBs can interfere with the ontogeny of the
kisspeptin system. Because PCBs are present in the environment and the body as
mixtures, the impacts of two different PCB mixtures were examined. The fi rst,
Aroclor 1221, was a popular commercial mixture composed of lightly chlorinated
PCB congeners with a half-life on the order of days. The second consisted of a
reconstituted PCB mixture containing three heavily chlorinated PCB congeners
(PCB138, PCB153, and PCB180) with half-lives on the order of decades and known
to bioaccumulate in the environment and human tissues [
109
,
110
]. Exposure on
only two days of late gestation (gestational days 16 and 18) to 1 mg/kg of either
mixture resulted in signifi cantly elevated preoptic levels of the kisspeptin receptor
(
Kiss1r,
previously identifi ed as GPR54) in females but reduced levels in males, by
the day of birth. This effect is likely estrogenic because it was recapitulated by ges-
tational EB exposure in both sexes [
111
].
A cohort of offspring were subsequently reared through young adulthood and
irregular estrous cycles were observed in both PCB exposed groups [
112
]. The ova-
ries appeared healthy, suggesting an overall disruption within the neural aspects of
the HPG axis. The density of kisspeptin-ir fi bers in the AVPV/PeN was signifi cantly
reduced by both PCB mixtures and to the same degree as EB, indicating masculin-
ization. Correspondingly, the percentage of GnRH neurons co-expressing FOS on
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