REDUCING ENVIORNMENTALLY INDUCED BIRTH DEFECTS WITH PRENATAL SUPPLEMENTION

Abstract

Pollutant exposure during development has been shown to induce developmental malformations. For example, penis deformities are the most common birth defects occurring in boys born in the United States, and are associated with exposure to endocrine disrupting chemicals. Hypospadias occurs when the urethra does not open at the distal tip of the penis, but rather along the shaft, and is associated with decreased anogenital distance (AGD). The incidence rate of hypospadias has doubled over the past 50 years. Currently there are no known prenatal supplements to protect the fetus from hypospadias-inducing pollutants. However, if we can up-regulate endogenous detoxifying enzymes within the mother, fetus, or placenta we should reduce the effects of toxicants on the fetus. It has been proposed that sulforaphane, a derivative of broccoli, could be developed as such a preventative prenatal supplement because of its ability to increase detoxification and decrease oxidative stress. Removal of the pollutant from maternal and fetal circulation before it can impact development is a viable and general method to reduce pollutant-induced diseases. Indeed, sulforaphane supplementation to pregnant mice exposed to the anti-androgen vinclozolin at concentrations (125 mg/kg) that demasculinize genital development can increase AGD, and reduce hypospadias severity (most effective sulforaphane dose is 45 mg/kg). Here I test the hypothesis that sulforaphane at 45 mg/kg can decrease the potency of vinclozolin. To test this I conducted a dose response experiment were I dosed pregnant CD1 mice with either 0 or 45 mg/kg of sulforaphane and crossed those doses with either 0, 50, 75, 100, and 125 mg/kg of Vinclozolin and measured hypospadias incidence and severity, and proximal urethral opening size. Sulforaphane exposure significantly lowered the dose response to vinclozolin across all endpoints. This work shows that sulforaphane can reduce the severity and incidence of hypospadias in the mouse model, and takes the first step required to develop a prenatal supplement that will protect humans from pollutant-induced birth defects.