Dose-dependent acceleration in the delayed effects of neonatal oral exposure to low-dose 17α-ethynylestradiol on reproductive functions in female Sprague-Dawley rats

Abstract

-Xenoestrogen exposure during the critical period of sexual differentiation of the brain causes delayed effects on female reproduction. We investigated the internal dose of orally administered ethynylestradiol (EE) during the critical period and its delayed effects by administering 0 (vehicle control), 0.4, or 2 μg/kg EE to female Sprague-Dawley rats for 5 days from postnatal day (PND) 1. Determination of serum EE level 24 hr after the initial dosing and 6 and 24 hr after the final dosing of 2 μg/kg indicated that the administered EE entered the circulation and cleared after every administration. Although the treatment did not affect physical development, including growth, eyelid opening, and vaginal opening, the estrous cycle was arrested from postnatal week (PNW) 12 even with 0.4 μg/kg EE, with an inverse correlation between doses and arresting ages. Although ovarian morphology at PNW 22-23 indicated that the treatment caused long-term anovulation and cystic follicle formation, the number of primordial follicles at PNW 22-23 was similar among the groups. Because this number was lower than that at PND 10 in all groups, primordial follicles may have been consumed under long-term anovulation. The treatment also caused other abnormalities, including mammary gland hyperplasia, increase in pituitary and liver weights, and decrease in the uterine weight. Because the highest circulating EE level in the 2 μg/kg-treated neonates is considered to be comparable to the physiological range of estradiol-17β, we concluded that a slight increase in the circulating estrogens during the neonatal period exerts irreversible delayed effects.

Normal ovarian aging, but modified T-cell differentiation, in female mice following neonatal exposure to bisphenol A

“…Previously, we demonstrated that neonatal exposure to diethylstilbestrol (DES) accelerated onset of abnormal estrous cycles in female Sprague-Dawley (SD) rats (Ohta et al, 2012a) and female C57BL/6J mice (Ohta et al, 2014) as they aged, suggesting the importance of observing estrous cycles over a long period in research on endocrine disrupting chemicals (EDCs). Similarly, other investigators suggested that neonatal exposure to DES in Donryu rats (Yoshida et al, 2011) and to 17alpha-ethynylestradiol in SD rats (Shirota et al, 2012;Shirota et al, 2015) or Wistar Hannover rats (Takahashi et al, 2013) induced delayed effects on their estrous cycles. It was proposed that abnormal development of kisspeptin neurons plays a key role in early onset of abnormal estrous cycles in rats (Ichimura et al, 2015;Takahashi et al, 2016).…”

Prenatal and pubertal exposure to 17α-ethinylestradiol disrupts folliculogenesis and promotes morphophysiological changes in ovaries of old gerbils (Meriones unguiculatus)

“…Previous studies have already demonstrated the influence of ethinylestradiol on the stages of estrous cycle of female rodents, with delay or late onset being observed in females exposed to certain concentrations of exogenous estradiol analogs. 55 Among the endocrine mechanisms involved in the development and maintenance of the corpus luteum, the elevated plasma estrogen concentration from the preovulatory follicle stands out as a preponderant factor, as it determines a preovulatory peak of LH and, consequently, ovulation and luteinization. Likewise, estradiol is also related to the degeneration of the structure of the corpus luteum, since they are related to the secretion of PGF2-a, a substance responsible for, among other effects, decreasing blood flow to the corpus luteum and degeneration of its capillaries.…”

“…Likewise, estradiol is also related to the degeneration of the structure of the corpus luteum, since they are related to the secretion of PGF2-a, a substance responsible for, among other effects, decreasing blood flow to the corpus luteum and degeneration of its capillaries. 13,55,56 In gerbils, females that have not copulated present a rapid involution of the corpus luteum within 3 to 6 days after their formation. However, remaining luteal cells may be present for longer periods of time.…”

Developmental exposure to low levels of ethinylestradiol affects social play in juvenile male rats

“…In fact, in fishes, EE 2 is concentrated multiple times (480-720) relative to water [35]. Studies on terrestrial mammals at concentrations similar to the contraceptive dose of 400-800 ng/kg/day or lower are relatively scarce: administration of EE 2 during development can affect a variety of reproductive anatomical and physiological endpoints in mice and rats [20,[36][37][38][39][40][41][42][43][44][45][46] but see a lack of effects with 500 ng/kg/day in Mandrup et al [34].…”