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Gestational and Lactational Exposure to Ethinyl Estradiol, but not Bisphenol A, Decreases Androgen-Dependent Reproductive Organ Weights and Epididymal Sperm Abundance in the Male Long Evans Hooded Rat.
Citation:
HOWDESHELL, K., J. R. FURR, C. R. LAMBRIGHT, V. S. WILSON, B. C. RYAN, AND L. E. GRAY. Gestational and Lactational Exposure to Ethinyl Estradiol, but not Bisphenol A, Decreases Androgen-Dependent Reproductive Organ Weights and Epididymal Sperm Abundance in the Male Long Evans Hooded Rat. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 102(2):371-382, (2008).
Impact/Purpose:
The importance of this study is two-fold. First, we demonstrated that prenatal and gestational exposure to ethinylestradiol (EE) can have permanent effects on male reproductive morphology and physiology in the LE rat. EE has recently been identified as a candidate for criteria derivation by the US EPA, Office of Water for its endocrine-disruptive effects on aquatic species (Joseph Beaman, personal communication). The interest in EE by the US EPA is timely as a recent study reported that chronic exposure to a dose of EE 1000-fold lower than the lowest effective dose used in our rat study (5 ng/L) resulted in abnormal gonadal development in the fathead minnow, which ultimately lead to near extinction of this species from the test lake (Kidd et al., 2007). Secondly, our study addressed many of the criticisms of previous low dose research on bisphenol A; namely, we used a positive control (EE), a non-Sprague-Dawley rat model (LE rat strain), and oral route of exposure. The use of the positive control over a dose range of high to low doses allowed us to look for non-monotic dose responses (which we did not find at the doses tested) and to evaluate the sensitivity of the LE rat to synthetic estrogen exposure. The use of a non-Sprague-Dawley strain was informative as the Sprague-Dawley rat had been identified by some scientists as less sensitive to synthetic steroid hormone exposure (Richter et al., 2007). Interestingly, we observed effects on male organ weights and sperm counts with EE doses of 5 to 50 µg/kg/dy in the male LE rat that were in contrast to lack of EE effects on male reproductive tract development in the CD(Sprague Dawley)IGS BR rat strain reported by Sawaki et al. (2003); the difference in EE effects between these studies could be due to differences in rat strain or laboratory procedures. Finally, humans are most likely exposure to EE and bisphenol A orally, thus oral exposure was deemed the most relevant route of administration.
Description:
Many chemicals released into the environment are capable of disrupting normal sex steroid balance, including the oral contraceptive ethinyl estradiol (EE) and the plastic monomer bisphenol A (BPA). EE and BPA are reported to impair reproductive organ development in laboratory animals; however, effects of lower doses of these chemicals have been debated. The goal of the current study was to determine whether relatively low oral doses of EE or BPA would alter male reproductive morphology and associated hormone levels of Long Evans hooded rat. Dams were gavaged with corn oil vehicle, EE (0.05-50 mug/kg/day) or BPA (2, 20, and 200 mug/kg/day) during pregnancy through lactation from gestational day 7 to postnatal day (PND) 18. Anogenital distance was measured at PND2 and nipple retention was measured at PND14 in male pups. Male offspring were euthanized beginning at PND150, and sera and organs were collected for analyses. Adult body weight was significantly decreased in males exposed to 50 mug EE/kg/day. Developmental EE exposure reduced androgen-dependent tissue weights in a dose-dependent fashion; for example, seminal vesicle and paired testes weights were reduced with >/= 5 mug EE/kg/day. Epididymal sperm counts were also significantly decreased with 50 mug EE/kg/day. In contrast, treatment with 2, 20, or 200 mug BPA/kg/day or EE at 0.05-1.5 mug/kg/day did not significantly affect any male endpoint in the current study. These results demonstrate that developmental exposure to oral micromolar doses of EE can permanently disrupt the reproductive tract of the male rat.
