Effects of in Utero Tributyltin Chloride Exposure in the Rat on Pregnancy Outcome

Abstract

Tributyltin, an organotin, is ubiquitous in the environment. The consumption of contaminated marine species leads to human dietary exposure to this compound. Tributyltin is an endocrine disruptor in many wildlife species and inhibits aromatase in mammalian placental and granulosa-like tumor cell lines. We investigated the effects of tributyltin chloride exposure on pregnancy outcome in the Sprague-Dawley rat. Timed pregnant rats were gavaged either with vehicle (olive oil) or tributyltin chloride (0.25, 2.5, 10, or 20 mg/kg) from days 0-19 or 8-19 of gestation. On gestational day 20, dams were sacrificed, and pregnancy outcome was determined. Tributyltin and its metabolites (dibutyltin, monobutyltin) were measured in maternal blood by gas chromatography. Both tributyltin and dibutyltin were present in maternal blood at approximately equal concentrations, whereas monobutyltin contributed minimally to total organotins. Organotin concentrations increased in a dose-dependent pattern in dams, independent of the window of exposure. Tributyltin chloride administration significantly reduced maternal weight gain only at the highest dose (20 mg/kg); a significant increase in post-implantation loss and decreased litter sizes, in addition to decreased fetal weights, was observed in this group. Tributyltin chloride exposure did not result in external malformations, nor was there a change in sex ratios. However, exposure to 0.25, 2.5, or 10 mg/kg tributyltin chloride from gestation days (GD) 0-19 resulted in a significant increase in normalized anogenital distances in male fetuses; exposure from days 8-19 had no effect. There was a dramatic increase in the incidence of low weight (< or =0.75 of the mean) fetuses after exposure to 20 mg/kg tributyltin chloride. Delayed ossification of the fetal skeleton was observed after in utero exposure to either 10 mg/kg or 20 mg/kg tributyltin chloride. Serum thyroxine and triiodothyronine levels were reduced significantly in dams exposed to 10 and 20 mg/kg tributyltin chloride throughout gestation; in dams treated with tributyltin from GD 8-19, serum thyroxine concentrations, but not triiodothyronine, were significantly decreased at both the 2.5 and 10 mg/kg exposures. Thus, maternal thyroid hormone homeostasis may be important in mediating the developmental toxicity of organotins.

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

“…Transplacental transfer of TBT has been documented [22]. In rats, studies from our group and others have shown that in utero exposure to high doses of TBT led to decreased maternal weight gain and fetal weights, induced pre-or post-implantation losses [16,[23][24][25] and caused fetal toxicity [26]. Although gestational exposure to TBT altered anogenital distance in both postnatal day 1 female pups [27] and gestational day 20 male rat fetuses [16], sex ratio was not altered in these studies.…”

“…It is plausible that this increased expression reflects at least in part, an increase in mRNA stability, an adaptation of the organism to stress that negatively affects translation [51], in this case, TBT, a known inhibitor of protein synthesis. These fetuses showed significantly smaller weights than controls (even though their placentas were bigger) and delayed bone ossification [16], an indication of a sub-optimal intrauterine environment. Interestingly, in the ovaries of littermates, eight genes were downregulated, suggesting that TBT-induced changes in gene expression patterns are gonad-specific; this observation reiterates the potential gender-specific effects of in utero exposure to toxicants [52].…”

“…Our quantitative analysis of the number of gonocytes/unit area of the seminiferous tubules revealed a significant decrease only at a maternal dose of 10 mg/kg (days [8][9][10][11][12][13][14][15][16][17][18][19]. However, both doses and exposure periods resulted in a reduction in the numbers of Sertoli cells, an effect which could potentially reduce sperm production in adulthood.…”

“…Immunotoxic effects of TBT include atrophy of the thymus and spleen, decreased T-lymphocyte populations, suppression of natural killer cell activity, and lowered resistance to infections in rats and mice [13][14][15]. TBT can also alter circulating levels of thyroid hormones suggesting that it can significantly alter many developmental processes that are thyroid-hormone dependant, including the reproductive system [16,17].…”

“…Given the effects of TBT on the functions of a wide range of mammalian cells and organs, in the current study we investigated the consequences of exposure to TBT during pregnancy on the histology and gene expression profiles of fetal gonads. In a previous study, we reported the effects of the same dosing regimen on TBT concentrations in maternal blood, maternal weight gain and pregnancy outcome [16].…”