In utero exposure to tributyltin chloride differentially alters male and female fetal gonad morphology and gene expression profiles in the Sprague–Dawley rat

Tributyltin (TBT) is an environmental contaminant commonly used in anti-fouling agents for boats, as well as a by-product from several industrial processes. It has been shown to accumulate in organisms living in areas with heavy maritime traffic thereby entering the food chain. Here, we determined the consequences of in utero exposure to TBT on the developing fetal gonads in the Sprague–Dawley rat. Timed pregnant rats were gavaged either with vehicle or TBT (0.25, 2.5, 10 or 20 mg/kg) from days 0 to 19 or 8 to 19 of gestation. On gestational day 20, dams were sacrificed; fetal testes and ovaries were processed for light (LM) or electron microscopic (EM) evaluation and RNA was prepared for gene expression profiling. At the highest doses of TBT the number of Sertoli cells and gonocytes was reduced, there were large intracellular spaces between Sertoli cells and gonocytes and there was an increased abundance of lipid droplets in the Sertoli cells; EM studies revealed abnormally dilated endoplasmic reticulum in Sertoli cells and gonocytes. In the intertubular region between adjacent interstitial cells, immunostaining for the gap junctional protein connexin 43 was strong in controls, whereas it was reduced or completely absent in treated rats. In the ovaries, TBT (20 mg/kg, days 0–19; 10 mg/kg, days 8–19) reduced the number of germ cells by 44% and 46%, respectively. On examining gene expression profiles in the testis, 40 genes out of 1176 tested were upregulated more than two-fold over control. While no genes were upregulated in the TBT exposed fetal ovary, eight genes were downregulated. In conclusion, in utero exposure to TBT resulted in gender-specific alterations in gonadal development and gene expression profiles suggesting that there may be different adaptive changes to toxicity in developing male and female rats.