Effects of Environmental Endocrine Disruptors and Phytoestrogens on the Kisspeptin System - Kisspeptin Signaling in Reproductive Biology - page 453

and sexually dimorphic at birth (higher in females) and then equivalent by postnatal
day (PND) 19 and thereafter [ 87 , 90 ]. The functional signifi cance of this transient
early life sex difference remains to be determined. Exogenous administration of
estrogens, or aromatizable androgens, during the neonatal critical period produces
the male phenotype [ 91 , 92 ], demonstrating that this is a particularly sensitive win-
dow of vulnerability to endocrine disruption and that organizational changes are
likely to be permanent.
Although a small subset of AVPV/PeN kisspeptin neurons co-express ER in females

[ 93 , 94 ], suggesting that either ER subtype could contribute to the estrogen-dependent
sex-specifi c ontogeny and function of the kisspeptin system, it is generally accepted that
ER

β

is the primary ER isoform mediating estrogen activity on kisspeptin neurons. This
is particularly clear in the AVPV/PeN. Estradiol administration successfully stimulates
AVPV/PeN kisspeptin neurons in ER

α

β knockout mice but not in ER α knockout mice

[ 93 ]. Additionally, a role for ER in the masculinization of the AVPV/PeN kisspeptin

system is suggested by the observation that neonatal administration of the ER

α

α -selective

agonist PPT, but not the ER -selective agonist DPN, results in abrogated AVPV/PeN

Kiss1 mRNA levels [ 95 ] and immunoreactive (−ir) fi bers [ 96 ] in female rats. Thus,
EDCs with the capacity to interact with ER

β

, or its expression, presumably have the
greatest potential to disrupt the sex-specifi c ontogeny and function of the AVPV/PeN
aspect of the kisspeptin system. In the ARC, steroid action is more complex and may be
conferred by other routes including the androgen receptor and “nonclassical” estrogen
signaling pathways [ 97 ]. For example, ARC Kiss1 expression is suppressed by neonatal
administration of E2, but not ligands selective for ER

α

, suggesting that the E2
effect must be mediated via a “nonclassical” pathway (Fig. 21.3 ) [ 95 ]. These regional
differences in E2 signaling within the kisspeptin system suggest that endocrine disrup-
tors could have region-specifi c effects, and that compounds capable of interacting with
membrane ERs may specifi cally modulate the ARC population of kisspeptin neurons.
Comparatively less is known about the MeA population of kisspeptin neurons. It is
sexually dimorphic in mature rodents, with higher levels of Kiss1 in males (Table 21.2 )
[ 79 ]. Similar to the AVPV/PeN population, Kiss1 expression in the MeA appears to be
exclusively driven by ERs because estradiol, but not the non-aromatizable androgen
DHT, modulates expression [ 79 ]. The functional role of this population remains to be
elucidated, although it is hypothesized to be involved in coordinating responses to
pheromonal and other olfactory cues related to social and reproductive behavior.

α or ER β

BPA Effects on the Rodent Kisspeptin System

Females

Exposure to BPA has been shown to impact female reproductive physiology in numer-
ous rodent models (reviewed in [ 16 ]). Effects include accelerated female puberty,
irregular estrous cycles, and premature anestrous. These effects could result from
disruption anywhere within the hypothalamic pituitary gonadal (HPG) axis, from the