Mechanisms of action of phthalate esters, individually and in combination, to induce abnormal reproductive development in male laboratory rats

Phthalate esters are high production volume chemicals used to impart flexibility to polyvinyl chloride products as well as other applications. In the male laboratory rat, the period of sexual differentiation in utero is particularly sensitive to certain phthalate esters, which induce a suite of reproductive malformations, including epididymal and gubernacular agenesis. The fetal rat testes are a main target for phthalate esters as evidenced by a reduction in testosterone production and insulin-like hormone 3 (insl3) expression, a peptide hormone critical for testis descent. Histopathology of fetal and postnatal testes reveals that in utero exposure to phthalate esters disrupts Leydig and Sertoli cell maturation leading to a reduction in germ cells in the malformed seminiferous tubules in adulthood as well as an increased incidence of multinucleated germ cells. There are some strain-specific differences in the target organs in the male reproductive tract in rats affected by phthalate esters. Mixtures of phthalate esters with one another and with other anti-androgenic compounds exhibit cumulative, largely dose-additive effects on male reproductive tract development when administered during sexual differentiation in utero. Since phthalate ester metabolites are detected in maternal and fetal body fluids, and androgen-signaling and insl3 are highly conserved among mammals, phthalates may potentially affect human reproductive development.