Adeeko Adedayo, Li Daming, Forsyth Don S, Casey Valerie, Cooke Gerard M, Barthelemy Johanna, Cyr Daniel G, Trasler Jacquetta M, Robaire Bernard, Hales Barbara F
Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada H3G 1Y6.
Toxicol Sci. 2003 Aug;74(2):407-15. doi: 10.1093/toxsci/kfg131. Epub 2003 May 28.
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.
三丁基锡是一种有机锡，在环境中广泛存在。食用受污染的海洋物种会导致人类通过饮食接触到这种化合物。三丁基锡是许多野生动物物种的内分泌干扰物，并能抑制哺乳动物胎盘和颗粒样肿瘤细胞系中的芳香化酶。我们研究了氯化三丁基锡暴露对斯普拉格-道利大鼠妊娠结局的影响。在妊娠第0至19天或第8至19天，对定时受孕的大鼠分别灌胃给予赋形剂（橄榄油）或氯化三丁基锡（0.25、2.5、10或20 mg/kg）。在妊娠第20天，处死母鼠并确定妊娠结局。通过气相色谱法测定母血中的三丁基锡及其代谢产物（二丁基锡、单丁基锡）。母血中三丁基锡和二丁基锡的浓度大致相等，而单丁基锡在总有机锡中所占比例极小。母鼠体内有机锡浓度呈剂量依赖性增加，与暴露窗口无关。仅在最高剂量（20 mg/kg）时，氯化三丁基锡给药显著降低了母鼠体重增加；该组观察到着床后损失显著增加、窝仔数减少以及胎儿体重下降。氯化三丁基锡暴露未导致外部畸形，性别比例也无变化。然而，在妊娠第0至19天暴露于0.25、2.5或10 mg/kg氯化三丁基锡会导致雄性胎儿的标准化肛门生殖器距离显著增加；第8至19天暴露则无影响。暴露于20 mg/kg氯化三丁基锡后，低体重（≤平均体重的0.75）胎儿的发生率显著增加。在子宫内暴露于10 mg/kg或20 mg/kg氯化三丁基锡后，观察到胎儿骨骼骨化延迟。在整个妊娠期暴露于10和20 mg/kg氯化三丁基锡的母鼠中，血清甲状腺素和三碘甲状腺原氨酸水平显著降低；在妊娠第8至19天用三丁基锡处理的母鼠中，在2.5和10 mg/kg暴露剂量下，血清甲状腺素浓度显著降低，但三碘甲状腺原氨酸浓度未降低。因此，母体甲状腺激素稳态可能在介导有机锡的发育毒性中起重要作用。
