Persistent Impairment of Hypothalamic KiSS-1 System after Exposures to Estrogenic Compounds at Critical Periods of Brain Sex Differentiation

Abstract

Attainment of reproductive capacity at puberty relies on a complex series of maturational events that include sexual differentiation of the brain; a hormonally driven phenomenon that takes place at early stages of development (critical period). Alterations of sex steroid milieu during such critical period disrupt pubertal maturation and gonadotropic function later in life, through mechanisms that remain partially unknown. Kisspeptins, products of the KiSS-1 gene acting via G protein-coupled receptor 54, have recently emerged as essential gatekeepers of puberty onset and reproductive function. By using rat models of neonatal administration of estrogenic compounds, we provide herein compelling evidence for the functional impairment of the hypothalamic KiSS-1 system at the time preceding puberty after early inappropriate exposures during brain sex differentiation. Neonatal injection of estradiol benzoate to male and female rats resulted in a dose-dependent decrease in hypothalamic KiSS-1 mRNA levels at the prepubertal stage, linked to lowering of serum LH concentrations. Yet, despite persistently decreased basal gonadotropin levels in estrogenized animals, intracerebral injection of kisspeptin evoked potent LH and FSH secretory responses, similar in magnitude to those of control animals. Estrogenized rats also showed defective levels of hypothalamic KiSS-1 mRNA and circulating gonadotropins in response to gonadectomy, whereas exogenous kisspeptin was capable to enhance further LH and FSH secretion in this model. Finally, protocols of neonatal exposure to high doses of an environmentally relevant estrogen, bisphenol-A, mimicked the effects of estradiol benzoate in terms of hypothalamic expression of KiSS-1 gene at the prepubertal period. Altogether, our data document the sensitivity of the hypothalamic KiSS-1 system to alterations in sex steroid milieu during critical periods of brain sex differentiation, and suggest that lowering of endogenous kisspeptin tone induced by early exposures to xeno-estrogens might be mechanistically relevant for disruption of gonadotropin secretion and puberty onset later in life.

Kisspeptin signalling and its roles in humans

“…In rats, neonatal exposure to oestrogenic compounds suppressed kisspeptin production in the peripubertal and adult stages. (52,84,85) This resulted in HH, which resolved with exogenous kisspeptin. In neonatal female rats, exposure to androgenic compounds led to reduced kisspeptin production by the AVPV during adulthood.…”

Early indicators of delayed adverse effects in female reproductive organs in rats receiving neonatal exposure to 17alpha-ethynylestradiol

“…Only Kiss1 showed a significant decrease in all of the EEtreated groups at PND14. Neonatal injection of estradiol benzoate to male and female rats results in a dose-dependent decrease in hypothalamic Kiss1 mRNA levels in the prepubertal stage (Navarro et al, 2009). Therefore, a significant decrease of Kiss1 mRNA at PND14 might be induced by neonatal exposure to EE.…”

Delayed Adverse Effects of Neonatal Exposure to Diethylstilbestrol and Their Dose Dependency in Female Rats

“…832 YOSHIDA ET AL. TOXICOLOGIC PATHOLOGY impairment of female reproductive functions (Bateman and Patisaul 2008;Navarro et al 2009). Kisspeptin and its signaling pathway in GnRH neurons might be anticipated as key factors in delayed effects.…”