Biology Reference
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function could be a central mechanism by which exposure to an estrogenic endocrine
disruptor, such as BPA, induces a suite of reproductive effects.
The fi rst indication that the kisspeptin system could be vulnerable to endocrine
disruption was reported in 2009. Subcutaneous injection of 100 or 500
g BPA
between PNDs 1 and 5 resulted in reduced hypothalamic
Kiss1
levels on PND 30 in
rats of both sexes [
91
]. In males, this effect persisted through PND 75 and was
accompanied by a persistent decrease in basal LH levels, suggesting that steroid
negative feedback on gonadotropin secretion was impaired. This effect implicates
the ARC as the site of disruption, a possibility that could not be delineated from this
initial study because
Kiss1
expression was quantifi ed in whole hypothalamus. Thus,
it remained unclear which population of
Kiss1
neurons BPA impacted: AVPV/PeN,
ARC, or both. This study used relatively high doses of BPA which are not relevant
when considering the potential impacts of human exposure. Importantly, however,
it established the “proof of principle” that the kisspeptin system could be impacted
by EDCs. It also identifi ed the neonatal critical period as a vulnerable exposure
window, and demonstrated that both sexes are at risk.
A subsequent series of papers provided the fi rst piece of evidence that BPA
effects on the kisspeptin system could be region and sex specifi c. Newborn rats were
subcutaneously injected with BPA (50
μ
g/kg or 50 mg/kg) daily for the fi rst four
days of life. Estradiol benzoate (EB) was used as a positive control because it is well
established that estrogen administration during this critical period masculinizes the
HPG axis. Consistent with what had been published previously [
100
], females
exposed to the lower dose displayed early vaginal opening, a hallmark of puberty in
the rat, and females in both exposure groups developed irregular estrous cycles
[
101
]. The animals were then ovariectomized and sequentially administered EB and
progesterone over 48 h to stimulate a gonadotropin surge [
102
]. GnRH activation,
assessed by quantifying the co-localization of GnRH and FOS, in both BPA expo-
sure groups was as robust as in the unexposed controls, suggesting that BPA did not
masculinize this aspect of the HPG axis. Accordingly, the density of kisspeptin-ir
fi bers in the AVPV/PeN was not signifi cantly impacted by BPA exposure but sig-
nifi cantly lower in females masculinized by EB [
96
].
By contrast, in the ARC, the plexus of kisspeptin-ir fi bers was less dense in the
50 mg/kg BPA exposed females, an observation consistent with impaired steroid
negative feedback and may account for the observed estrous cycle irregularities.
A potential limitation of these studies, however, is the use of kisspeptin-ir fi bers as
a marker of kisspeptin content. This was done because the soma do not readily label
in the rat, particularly in the AVPV/PeN. A subsequent study by this group showed
that the magnitude of the sex difference in kisspeptin-ir fi bers closely mirrors that of
Kiss1
mRNA in the AVPV/PeN [
88
]. By contrast, although the sex difference in the
density of ARC kisspeptin-ir fi bers is pronounced by weaning, there is no sex dif-
ference in the number of kisspeptin-ir soma or
Kiss1
expression [
88
,
89
]. An incom-
plete understanding of the functional relevance of the sex difference in ARC fi ber
density makes the impact of EDCs on this aspect of the kisspeptin system diffi cult
to interpret. One possibility is that elevated fi ber labeling in females results from
increased kisspeptin storage or transport. Conversely, kisspeptin secretion could be
μ
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