Teratogenic effects of in utero exposure to Di-(2-Ethylhexyl)-Phthalate (DEHP) in B6:129S4 Mice

Abstract

Intrauterine exposure to phthalates is known to cause disorders ofmale reproductive function including androgen insufficiency, decreased fertility, and germ cell defects in rodents. In this study, we set out to investigate the effects of intrauterine exposure to di-(2-ethylhexyl)-phthalate (DEHP) on fetal development of the B6:129S4mouse strain. Time-mated pregnant C57BL/6 dams were exposed to 0, 5, 250, or 500mg/kg DEHP with corn oil as the vehicle via oral gavage fromembryonic days (E)7 to 16. Survival and grossmorphology of the pups were analyzed one day after the last treatment. Anogenital distance (AGD) and testicular cell functions were examined inmale embryos to confirm the known effects of phthalate exposure. DEHP exposure significantly reduced the survival rate of fetuses in the 250 and 500mg/kg dosage groups compared with the control and 5mg/kg groups. Exposure to 250 and 500mg/kg DEHP was teratogenic and induced exencephaly and limbmalformations such as polydactyly in the B6:126S4 embryos. No gross malformations were observed in control or 5mg/kg DEHP groups. Inmale embryos, exposure to both 5 and 250mg/kg DEHP in utero was sufficient to induce the formation ofmultinucleated germ cells in the testes and widespread changes in mRNA expression of germ cell, interstitiumand Sertoli cell-associated genes. These findings reveal that intrauterine DEHP exposure has a strong teratogenic, and lethal impact on the fetuses of B6:129S4mouse strain.