Biology Reference
In-Depth Information
Similar to what has been reported for the PCBs, developmental exposure to
GEN, an isofl avone found in soy and other legumes, has a masculinizing infl uence
on the rat female kisspeptin system (Table
21.2
). Early life exposure to GEN, like
BPA and the PCBs, advances female puberty and produces estrous cycle irregulari-
ties [
119
], implying disrupted ontogeny of the HPG axis. In female rats, neonatal
exposure to 10 mg/kg GEN, but not 1 mg/kg, resulted in a lower density of AVPV/
PeN kisspeptin-ir fi bers across the pubertal transition [
88
], an effect which persisted
into adulthood and is indicative of masculinization (Fig.
21.4
) [
119
]. In the ARC,
kisspeptin- ir fi ber density was unaltered by GEN but signifi cantly lessened by
developmental EB exposure [
88
,
119
]. Early life exposure to GEN also resulted in
impaired GnRH activation in ovariectomized, hormone replaced females [
119
], an
effect which is consistent with masculinization of AVPV/PeN kisspeptin signaling
pathways. Interestingly, the phytoestrogen metabolite equol did not confer a similar
suite of effects on the female kisspeptin system when administered at the same dose
[
119
], despite being considered a more potent estrogen agonist than GEN [
120
].
Moreover, no signifi cant impacts of postnatal GEN exposure were found on adult
male kisspeptin-ir levels [
96
]. The collective effects of developmental GEN expo-
sure are similar to those produced by PCBs and emphasize the sex-specifi c vulner-
ability of the kisspeptin system to other estrogenic EDCs.
From Endocrine Disruption to the Fetal Basis of Adult Disease
Since its conception in 1991, the EDC fi eld has rapidly gained a foothold in clinical
endocrinology, and this evolution has generated a provocative new idea: diseases of
adulthood may begin in the womb. This “Fetal Basis of Adult Disease” hypothesis
is an extension of the “Barker hypothesis” which predicted that individuals con-
ceived during times of stress and nutrient deprivation will develop a “thrifty” phe-
notype that effi ciently extracts and retains nutrients [
121
]. Disease results when this
phenotype is mismatched and the individual lives in conditions where nutrients are
abundant and thus becomes obese and prone to diabetes, cardiovascular disease, and
hypertension. It is now hypothesized that early life exposure to chemicals also con-
tributes to disease states that emerge later in life, particularly reproductive and met-
abolic disorders [
122
]. The impacts of smoking and alcohol on fetal development
have long been recognized and give credence to this hypothesis, but the long-term
impacts of seemingly more innocuous chemicals, such as those that leach from food
containers, coat our electronic devices, and escape from furniture into house dust
where we then eat and breathe them, remain unclear.
As exemplifi ed by the phytoestrogens, sensitivity to estrogenic chemicals would
be adaptive in the right context but also capable of conferring disease. Current evi-
dence supports the hypothesis that the kisspeptin system is a crucial component of
a complex neuroendocrine system, which senses environmental signals and responds
to optimize critical developmental stages including puberty, mate seeking, and preg-
nancy. For example, despite decades of research to unlock the “black box” that is
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