Effects of Prepubertal Zeranol Exposure on Estrogen Target Organs and N-Methyl-N-nitrosourea-induced Mammary Tumorigenesis in Female Sprague-Dawley Rats

Background: There are no previous reports of the effects of prepubertal exposure to zeranol, an estrogenic substance, on estrogen-responsive reproductive organs and mammary glands in rats, or its effects on N-methyl-N- nitrosourea (MNU)-induced mammary tumorigenesis in rats. Materials and Methods: Prepubertal female Sprague-Dawley rats were treated daily with either 0, 0.1 or 10 mg/kg body weight of zeranol between 15 and 19 days of age. They were given 50 mg/kg body weight MNU at 28 days of age, and were monitored for occurrence of mammary tumors ≥1 cm in diameter. Body weight gain, structures and functions of estrogen target tissues, and mammary carcinogenesis were compared between dosage groups. Results: Zeranol did not affect body weight gain. At 28 days of age, zeranol-treated and -untreated rats showed similar development of reproductive organs and mammary glands. However, both low- and high- dose zeranol treatment caused significantly earlier vaginal opening, irregularity of estrous cycle (high frequency of prolonged estrous or prolonged diestrous) at 8 to 11 weeks of age, and anovulatory ovary (ovaries without newly formed corpora lutea). At 37 weeks of age, the high-dose zeranol- treated group exhibited increased relative uterine-ovarian weight, but mammary gland development was comparable to that of untreated rats. Mammary carcinogenesis was not affected by low- or high-dose zeranol treatment. Conclusion: Short-duration zeranol treatment in the prepubertal period severely damaged ovarian functions and structure, but mammary carcinogenesis was not affected. The present results suggest that ingestion of foods containing zeranol in the infantile period can cause dramatic endocrine disruption in later life.