Developmental Exposure to Ethinylestradiol Affects Reproductive Physiology, the GnRH Neuroendocrine Network and Behaviors in Female Mouse.

Lyes Derouiche,Mariangela Martini,Anne H Duittoz,Matthieu Keller,Delphine Pillon

doi:10.3389/fnins.2015.00463

Abstract

During development, environmental estrogens are able to induce an estrogen mimetic action that may interfere with endocrine and neuroendocrine systems. The present study investigated the effects on the reproductive function in female mice following developmental exposure to pharmaceutical ethinylestradiol (EE2), the most widespread and potent synthetic steroid present in aquatic environments. EE2 was administrated in drinking water at environmentally relevant (ENVIR) or pharmacological (PHARMACO) doses [0.1 and 1 μg/kg (body weight)/day respectively], from embryonic day 10 until postnatal day 40. Our results show that both groups of EE2-exposed females had advanced vaginal opening and shorter estrus cycles, but a normal fertility rate compared to CONTROL females. The hypothalamic population of GnRH neurons was affected by EE2 exposure with a significant increase in the number of perikarya in the preoptic area of the PHARMACO group and a modification in their distribution in the ENVIR group, both associated with a marked decrease in GnRH fibers immunoreactivity in the median eminence. In EE2-exposed females, behavioral tests highlighted a disturbed maternal behavior, a higher lordosis response, a lack of discrimination between gonad-intact and castrated males in sexually experienced females, and an increased anxiety-related behavior. Altogether, these results put emphasis on the high sensitivity of sexually dimorphic behaviors and neuroendocrine circuits to disruptive effects of EDCs.

Highlights

Evidence that exposure to Endocrine Disrupting Chemicals (EDCs) during development contributes to disturbing various parameters of animal and human reproductive function, such as puberty onset, fertility, and behaviors, has been largely highlighted (Walker et al, 2014; Parent et al, 2015)
The present study investigated whether developmental sub-chronic exposure to an environmental-range or a pharmacological dose of EE2 from critical fetal and perinatal periods up to puberty disturbed reproductive function in adult female mice, including physiological and behavioral parameters, and neuroendocrine networks regulating the hypothalamic-pituitary-gonadal (HPG) axis
EE2 and Vaginal Opening Vaginal opening was detected from PND24 in 15 and 10% of the EE2-exposed females in the environmentally relevant (ENVIR) and PHARMACO groups respectively, whereas no vaginal opening was detected in CONTROL females (Figure 2B)

Summary

Introduction

Evidence that exposure to Endocrine Disrupting Chemicals (EDCs) during development contributes to disturbing various parameters of animal and human reproductive function, such as puberty onset, fertility, and behaviors, has been largely highlighted (Walker et al, 2014; Parent et al, 2015). It is widely accepted that natural hormones and potentially EDCs modulate the development of the central and peripheral nervous systems, including the setting of neuroendocrine circuits controlling physiological and behavioral outcomes of reproductive function (McCarthy, 2008; Gore et al, 2011). Hypothalamic neuroendocrine circuits orchestrating the pituitarygonadal activity are established during prenatal, early postnatal, and juvenile periods under the Ethinylestradiol and Female Gonadotropic Axis organizational effects of specific patterns of endogenous estrogens, leading to masculinization or feminization of a bipotential developing brain (McCarthy, 2008). Disruption of the ongoing patterns of estrogens during development may durably alter the establishment of neuroendocrine networks and affect physiological, neuroendocrine and behavioral components of reproductive function in adulthood

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