Toxicant-induced hypospadias in the male rat.

Abstract

Prenatal exposure to endocrine disrupting chemicals that interfere with the androgen or insulin like factor 3 signaling pathways during sexual differentiation can induce malformations of the reproductive tract of the male rodent offspring. The pattern of malformations in the male depends upon the specific mechanism of action of the toxicant, the dosage level administered and the timing of administration during pregnancy. Hypospadias occurs in male rats or mice after maternal treatment with 1). potent estrogens or estrogenic drugs, 2). drugs that inhibit 5 alpha reductase, 3). drugs, herbicides and dicarboximide and conazole fungicides that act as androgen receptor (AR) antagonists, and 4). drugs, herbicides and conazole fungicides that inhibit cytochrome P450 enzymes involved in steroid hormone synthesis. In addition, 5). several phthalate diesters including di-n-butyl phthalate (DBP), di-n-ethylhexyl phthalate (DEHP), and benzylbutyl phthalate(BBP) also induce hypospadias and by altering fetal testis Leydig cell differentiation, resulting in reduced steroid and peptide hormone production.