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