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

Abstract

-We previously reported that neonatal exposure to 17α-ethynylestradiol (EE) led to delayed adverse effects in which age-related anovulation after sexual maturation was accelerated. To identify early indicators of these adverse effects, female Wistar Hannover GALAS rats received a single EE injection (0, 0.02, 0.2, 2, 20, or 200 μg/kg) within 24 hr of birth. Histopathological changes in ovarian and uterine development were investigated from postnatal day (PND) 14 to 10 weeks of age. Immunohistochemical expression of estrogen receptor alpha (ERα) in the uterus, serum levels of sex-related hormones and gene expression in the hypothalamus were examined. Although neonatal exposure to EE did not affect body growth or ovarian development, serum FSH tended to decrease at doses  2 μg/kg, and Kiss1 mRNA level in the whole hypothalamus was significantly decreased in all EE-treated groups at PND14. The number of uterine glands at PND21 was suppressed at doses  20 μg/kg, and ERα expression in the uterine epithelium at estrus stage decreased in a dose-dependent manner at 10 weeks of age. These results demonstrated that the various identified changes that occurred before the appearance of delayed adverse effects could be candidate early indicators.

Effects of neonatal 17α-ethinyloestradiol exposure on female-paced mating behaviour in the rat

“…Previously, it has been reported that ERα expression was down‐regulated in both MPN and VMHvl in neonatal BPA‐exposed females (Monje et al, ). Using a similar protocol to that herein, a single neonatal ≥0.02 μg kg −1 EE‐treated female rats decreased ERα expression in the uterine epithelium at oestrus in a dose‐dependent manner (Takahashi et al, ). In addition, single neonatal exposure to 2 (HEE) and 0.02 mg kg −1 (LEE) EE decreased ERα expression in the hippocampus of adult female rats (Shiga et al, ), an effect also expected to occur in the hypothalamus.…”

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

“…However, it has been clearly established that the kisspeptin neuroendocrine network is highly dependent on gonadal steroids during postnatal development (Clarkson et al, 2009a ), and there is some growing evidence for the susceptibility of the kisspeptin neuroendocrine network to environmental pollution during the postnatal period (Franceschini and Desroziers, 2013 ). In female rats, perinatal exposure to 5, 15, or 50 μg/kg/d EE2 did not induce significant changes in kiss-1 mRNA levels in adulthood (Overgaard et al, 2013 ), as Takahashi et al ( 2014 ) found that a single injection of a low dose of 0.02 μg/kg EE2 at PND1 decreased hypothalamic Kiss-1 mRNA levels at PND14. In the present study, kisspeptin immunoreactivity was investigated in the PVpo, but not in the anteroventral periventricular (AVPV) nucleus or arcuate nucleus (Clarkson et al, 2009b ).…”

Prior attenuation of KiSS1/GPR54 signaling in the anteroventral periventricular nucleus is a trigger for the delayed effect induced by neonatal exposure to 17alpha-ethynylestradiol in female rats

“…Recently, our laboratory also identified that the rat neonatally exposed to various dose of EE showed the decreased FSH levels at PND14 and decreased ER␣ expression in the uterine epithelium at 10 weeks of age [44]. These early stage functional changes in the kisspeptin neuron, hormone balance and reproductive tissues might have the possibility to be the useful indicator for the delayed effects substitute for the abnormal estrous cycle occurred in later age, and may provide a new clue for the further investigation and risk identification of the delayed effect induced by the estrogenic chemicals like EDCs.…”