Long-Term Exposure of Female Sheep to Physiologic Concentrations of Estradiol: Effects on the Onset and Maintenance of Reproductive Function, Pregnancy, and Social Development in Female Offspring1

Abstract

As steroids and steroid-like compounds accumulate in the environment, it has become important to understand how low-dose exposure affects reproductive function. Ovary-intact sheep were used in a multigenerational study, to determine whether chronic exposure to low levels of estrogen disrupts reproductive function and behavior. We assessed parameters of reproductive performance in control and postnatally estradiol-treated females (Generation 1, G1), and their offspring (Generation 2, G2). In the G1 animals, 17beta-estradiol (E) was administered continuously from 4 wk of age at two doses via subcutaneous implants (ultralow E [<1 pg/ml in circulation, n = 8] or low E [1-3 pg/ml, n = 8]). Both doses delayed puberty; low E also produced pronounced prepubertal and seasonal anestrus hypogonadotropism, and delayed the onset of the second breeding season. All G1 animals conceived and produced offspring (G2), the treatment of which resulted from continuous maternal exposure during pregnancy and lactation. Behavioral observations of G2 females revealed that low prenatal E modestly masculinized play behavior and increased the frequency of attempts to displace competitors relative to ultralow E and control animals. The timing and magnitude of the LH surge also differed in prepubertal low prenatal E females relative to the controls, although these differences were not evident when retested at one year of age. These findings support the hypothesis that chronic exposure to physiologic amounts of exogenous estrogens has multigenerational effects on behavior and neuroendocrine function. Despite these disruptive steroid actions, ovarian cyclicity and fertility are not invariably compromised, pointing to an impressive resiliency of the reproductive axis to insult by exogenous estrogenic compounds.

Developmental programming: postnatal estradiol modulation of prenatally organized reproductive neuroendocrine function in sheep

“…Diminished gonadotropin release in response to E positive feedback was observed in prepubertal female sheep chronically treated with E in this study and in previous studies (Malcolm et al 2006). However, a reduction in periovulatory release of gonadotropins was not observed when examined during the first and second breeding season.…”

Developmental programming: Prenatal BPA treatment disrupts timing of LH surge and ovarian follicular wave dynamics in adult sheep

“…That LH surge responses normalize with reproductive maturity is also supported by our finding in ovariectomized prenatally BPA-treated females at 21 months of age, which showed a normal LH response to an exogenous estradiol administration (Abi Salloum et al, 2013). A similar outcome was achieved with prenatal estradiol treated sheep, namely reduction in LH surge amplitude when tested at 3.5 months of age, but not at 12 months of age (Malcolm et al, 2006). …”

Effect of prenatal androgens on click-evoked otoacoustic emissions in male and female sheep (Ovis aries)

“…0.46 cm; sealed with Silastic adhesive Type A, Dow-Corning Corp., Midland, MI) packed with crystalline 17β-estradiol (Sigma, St. Louis, MO) between days 30 – 90 of gestation. Past research revealed that the females receiving a lower dose of prenatal 17β-estradiol (13-mm silastic implant throughout the pregnancy) demonstrated an increase in aggressive displacement behavior as lambs and altered LH-surge properties prepubertally, but had a normal onset of puberty, normal postpubertal LH characteristics, and normal female-typical mating behavior (Malcolm et al, 2006). Because this estradiol-treated group consisted of only two animals, their data will be shown for completeness, but no statistical analyses will be reported.…”