Biologically relevant reductions in fetal testosterone and Insl3 induced by in utero exposure to high levels of di-isononyl phthalate (DINP) in male rats.

Some phthalate esters alter male rat reproductive development during sexual differentiation by interfering with fetal testis maturation resulting in reduced Leydig Cell synthesis of testosterone and insulin-like 3 (Insl3) hormones. Gene transcripts associated with steroid hormone and cholesterol transport, and cholesterol synthesis and lipid metabolism also are reduced. These alterations cause permanent malformations of hormone-dependent tissues, sperm production and fertility in male offspring; effects known as the "Phthalate Syndrome." We have shown that administration of a high dose of 750 mg diisononyl phthalate (750 mg/kg/d DINP) during sex differentiation reduced fetal testis testosterone production (T Prod), testis gene expression and induced a low incidence of reproductive malformations in male rat offspring. In the current study we administered DINP at even higher dose levels (1.0 and 1.5 g/kg/d) from gestational day (GD) 14 to postnatal (PND) 3 to determine if these effects were dose related and if the magnitude of the effects could be predicted from a statistical model of fetal testosterone production (T Prod) and Insl3 mRNA levels. These models were previously developed using dipentyl phthalate (DPeP) data from fetal T Prod and postnatal studies. We found that the severity of the demasculinizing effects on the androgen-dependent organs and gubernaculum by DINP were accurately predicted from the statistical models of fetal T prod and Insl3 mRNA, respectively. Taken together, our results indicate that reductions fetal T prod and Insl3 predict the severity of demasculinizing effects in utero exposure to the phthalates DINP and DPeP regardless of potency.