In Utero through Lactational Exposure to Ethinyl Estradiol Induces Cleft Phallus and Delayed Ovarian Dysfunction in the Offspring

• Published in: Toxicological sciences 2003-10, Vol.75 (2), p.402-411
• Main Authors: Sawaki, Masakuni, Noda, Shuji, Muroi, Takako, Mitoma, Hideo, Takakura, Saori, Sakamoto, Satoko, Yamasaki, Kanji
• Format: Article
• Language: English
• Subjects: Abnormalities, Drug-Induced; Animals; Biological and medical sciences; cleft phallus; delayed ovary dysfunction; Dose-Response Relationship, Drug; Drug toxicity and drugs side effects treatment; Embryology: invertebrates and vertebrates. Teratology; Estrogens - administration & dosage; Estrogens - toxicity; ethinyl estradiol; Ethinyl Estradiol - administration & dosage; Ethinyl Estradiol - toxicity; Female; Fundamental and applied biological sciences. Psychology; Genitalia, Female - abnormalities; Genitalia, Female - drug effects; Infertility, Female - chemically induced; Lactation; Male; Maternal Exposure; Medical sciences; Miscellaneous (drug allergy, mutagens, teratogens...); Ovary - drug effects; Ovary - pathology; Ovary - physiopathology; Pharmacology. Drug treatments; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Teratology. Teratogens
• ISSN: 1096-6080; 1096-0929; 1096-0929
• DOI: 10.1093/toxsci/kfg180

Most of the attention currently focused on endocrine-active chemicals is directed to their effects on the development of offspring exposed to them in utero or during the neonatal period. Pregnant Crj:CD(SD)IGS rats were given ethinyl estradiol (EE) orally in doses of 0.5–50 μg/kg/day from gestational day 7 to postnatal day 18, and their offspring were examined for its effects. Our previous study according to a similar protocol demonstrated the occurrence of cleft phallus in the female offspring exposed to 50 μg/kg of EE in utero and during the lactation period. The present study was designed to assess (1) the reproducibility of the induction of cleft phallus, (2) the fertility of female rats with cleft phallus, and (3) whether any delayed effects, possibly delayed anovulation, were induced. At 50 μg/kg cleft phallus was observed in almost all of the female offspring, and slight retardation of body weight gain was detected in both sexes. At 15–17 weeks of age the animals with cleft phallus could copulate and had fertility comparable to the control group. At 6 months of age, on the other hand, 6/8 of the female offspring at 50 μg/kg exhibited abnormal cyclicity, including persistent estrus, and histological examination revealed follicular cysts and absence of corpora lutea in the ovaries of the rats with persistent estrus. These findings are consistent with delayed anovulation syndrome. The results suggest that observation of cyclicity at 6 months old is able to detect possible delayed ovarian dysfunction induced by perinatal exposure to chemicals.