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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

Reproductive Sciences Program,³ Departments of Psychology,⁴ Pediatrics,⁵ Obstetrics and Gynecology,⁶ Molecular and Integrative Physiology,⁷ and Ecology and Evolutionary Biology,⁸ University of Michigan, Ann Arbor, Michigan 48109

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.

behavior, environment, estradiol, neuroendocrinology, puberty

¹Supported by research grants from the NIH (HD-18394 and HD-44232). Preliminary reports presented in part at the 36th Annual Meeting of the Society for the Study of Reproduction, Cincinnati, OH, July 19–22, 2003 (Abstract 381); and the 37th Annual Meeting of the Society for the Study of Reproduction, Vancouver, British Columbia, Canada, August 1–4, 2004 (Abstract 47).

Correspondence: ² Douglas L. Foster, Room 1101, 300 North Ingalls Building, University of Michigan, Ann Arbor, Michigan 48109-0404. FAX: 734 936 8620; e-mail: dlfoster{at}umich.edu

This article has been cited by other articles:

				L. M. Jackson, K. M. Timmer, and D. L. Foster Organizational Actions of Postnatal Estradiol in Female Sheep Treated Prenatally with Testosterone: Programming of Prepubertal Neuroendocrine Function and the Onset of Puberty Endocrinology, May 1, 2009; 150(5): 2317 - 2324. [Abstract] [Full Text] [PDF]

				E. K. Roberts, J. N. Flak, W. Ye, V. Padmanabhan, and T. M. Lee Juvenile Rank Can Predict Male-Typical Adult Mating Behavior in Female Sheep Treated Prenatally with Testosterone Biol Reprod, April 1, 2009; 80(4): 737 - 742. [Abstract] [Full Text] [PDF]