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ToxSci Advance Access originally published online on September 3, 2009
Toxicological Sciences 2009 112(2):331-343; doi:10.1093/toxsci/kfp207
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© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Mal-Development of the Penis and Loss of Fertility in Male Rats Treated Neonatally with Female Contraceptive 17{alpha}-Ethinyl Estradiol: A Dose-Response Study and a Comparative Study with a Known Estrogenic Teratogen Diethylstilbestrol

Ensa Mathews*, Tim D. Braden{dagger}, Carol S. Williams*, John W. Williams{ddagger}, Olga Bolden-Tiller§ and Hari O. Goyal*,1

* Department of Biomedical Sciences, College of Veterinary Medicine, Tuskegee University, Tuskegee, Alabama 36088 {dagger} Department of Anatomy, Physiology, and Pharmacology, Auburn University, Auburn, Alabama 36849 {ddagger} Department of Biology/Center for Biomedical Research/Research Center for Minority Institution § Department of Agricultural and Environmental Sciences, Tuskegee University, Tuskegee, Alabama 36088

1 To whom correspondence should be addressed. Fax: 334-727-8177. E-mail:goyalho{at}tuskegee.edu.

Received August 3, 2009; accepted August 25, 2009


  Abstract

The objectives of this study were to find a minimal dose of 17{alpha}-ethinyl estradiol (EE) that is detrimental to the developing penis and fertility and to compare estrogenic effects between EE and diethylstilbestrol (DES). Neonatal rats received EE at 10 ng (1 µg/kg), 100 ng, 1 µg, or 10 µg per pup on alternate days from postnatal days 1 to 11 (dose-response study) or received EE or DES at 100 ng per pup daily from postnatal days 1 to 6 (comparative study). Effects of EE were dose dependent, with ≥ 100-ng dose inducing significant (p < 0.05) reductions in penile length, weight, and diameter. Additionally, the penis was malformed, characterized by underdeveloped os penis and accumulation of fat cells. Fertility was 0% in the ≥ 1-µg groups, in contrast to 60% in the 100-ng group and 100% in the 10-ng and control groups. Animals treated with ≥ 10 ng had significant reductions in the weight of bulbospongious muscle, testis, seminal vesicle, epididymal fat pad, and in epididymal sperm numbers. A comparison of EE and DES effects showed similar reductions in penile weight and length and the weight of bulbospongiosus muscle, testis, seminal vesicle, epididymis, and epididymal fat pad in both adolescent and adult rats. While 5/6 control males sired, only 1/6 in the EE group and 0/6 in the DES group sired. Hence, neonatal exposure to EE at 10 ng (environmentally relevant dose) adversely affects male reproductive organs. A dose ten times higher than this leads to permanently mal-developed penis and infertility. Furthermore, EE and DES exposures show similar level of toxicity to male reproductive organs.

Key Words: ethinyl estradiol; DES; penis; development; toxicology.


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