ToxSci Advance Access originally published online on May 28, 2003
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Toxicological Sciences 74, 407-415 (2003)
Copyright © 2003 by the Society of Toxicology
REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY |
Effects of in Utero Tributyltin Chloride Exposure in the Rat on Pregnancy Outcome
* Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec H3G 1Y6;
Food Research Division, Health Products and Food Branch, Health Canada, Tunney’s Pasture, Ottawa, Ontario K1A 0L2;
Toxicology Research Division, Health Products and Food Branch, Health Canada, Tunney’s Pasture, Ottawa, Ontario K1A 0L2 and Departments of Cellular and Molecular Medicine, and Obstetrics and Gynecology, University of Ottawa, Ottawa, Ontario;
INRS-Institut Armand-Frappier, Université du Québec, 245 Hymus Boulevard Pointe Claire, Québec H9R 1G6;
¶ Departments of Pediatrics and Human Genetics, McGill University, Montreal, Quebec H3G 1Y6; and
|| Department of Obstetrics and Gynecology, McGill University, Montreal, Quebec H3G 1Y6
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 (
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.
Key Words: organotin; developmental toxicity; reproductive toxicity; fetal ossification; maternal thyroid status.
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