Methyl iodide-induced fetal hypothyroidism implicated in late-stage fetal death in rabbits

Abstract

Methyl iodide (MeI) induces fetotoxicity in New Zealand White (NZW) rabbits when maternal exposure occurs during a susceptible window late in gestation (gestation days [GD] 23–26). To identify the possible mode of action, comprehensive maternal and fetal bioanalysis and thyroid structure/function assessments were conducted in MeI-exposed (25 ppm by whole-body inhalation) and unexposed time-mated NZW rabbits (10/group) during GD 21–27. Key developmental events were observed within this window in unexposed fetuses, including the appearance of colloid in the thyroid follicular lumen and the detection of serum T₃ beginning on GD 22. Fetal T₄ and T₃ levels were diminished following maternal MeI exposure compared to baseline values. Fetal TSH was significantly increased following 4 days of maternal MeI exposure. MeI-induced changes in the fetal thyroid included reduced colloid formation, epithelial follicular hypertrophy, and epithelial cytoplasmic vacuolation. Time-course investigations using 20 ppm MeI revealed highly concentrated levels of iodide in fetal versus maternal serum. Direct maternal administration of sodium iodide by intravenous infusion during GD 23–26 induced similar effects on fetal thyroid structure and function as MeI, identifying iodide as the putative agent. Elevated S-methylcysteine adduct concentrations were noted in fetal hemoglobin, indicating that some unreacted MeI may be delivered directly to the fetus. However, the weight of evidence from these studies suggests that late-stage fetal death following maternal exposure to MeI during GD 23–26 is the result of preferential accumulation of iodide in the fetal compartment causing disruption of the fetal hypothalamic–pituitary–thyroid axis at a critical time in the development of the rabbit fetal thyroid.

Acknowledgements

This work has been presented in part at the Society of Toxicology Annual Meeting, March 2005.

This study was performed at WIL Research Laboratories, LLC, under the auspices of Arysta Life Sciences North America (formerly Arvesta Corporation). The authors thank Lewis E. Kaufman, MS (consultant to WIL Research, 123 Park Avenue, Wooster, OH, USA), for his help in the initial preparation of this article, including figures and tables, and Drs. Richard H. Bruner, DVM, DACVP, and Roxanne Baumgartner, DVM, DACVP, DABT, for histopathological evaluation of the thyroid tissues. The authors also acknowledge Dr. Matthew Himmelstein (DuPont Haskell Laboratory for Health and Environmental Science), Dr. Albert Parlow (Harbor-UCLA Medical Center, National Hormone and Peptide Program), Edward Kaiser (MPI Research, Inc.), Ray Kemper (formerly of DuPont Haskell Laboratory; currently at Boehringer-Ingelheim Pharmaceuticals, Inc.), and Diane Nabb (DuPont Haskell Laboratory) for their bioanalytical support (thyroid hormone, pituitary hormone, serum iodide, hemoglobin adduct, and glutathione analyses, respectively).

Declaration of interest: The authors report no conflicts of interest.