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Effects of Maternal Levels of Thyroid Hormone (TH) on the Hypothalamus-Pituitary-Thyroid Set Point: Studies in TH Receptor β Knockout Mice

Departments of Medicine (M.A., C.G., X.L., D.P., S.R., R.E.W.) and Pediatrics (S.R., R.E.W.), and Committees on Genetics (S.R.) and Molecular Medicine (S.R., R.E.W.), The University of Chicago, Chicago, Illinois 60637

Address all correspondence and requests for reprints to: Roy E. Weiss, M.D., Ph.D., The University of Chicago, MC 3090, Chicago, Illinois 60637. E-mail: rweiss{at}medicine.bsd.uchicago.edu.

A level of thyroid hormone (TH) in agreement with the tissue requirements is essential for vertebrate embryogenesis and fetal maturation. In this study we evaluate the immediate and long-term effects of incongruent intrauterine TH levels between mother and fetus using the TH receptor (TR) β^–/– knockout mouse as a model. We took advantage of the fact that the TRβ^–/– females have elevated serum TH but are not thyrotoxic due to resistance to TH. We used crosses between heterozygotes with wild-type phenotype (TRβ^+/–) males and TRβ^–/– females, with a hyperiodothyroninemic (high T₄ and T₃ levels) intrauterine environment (TH congruent with the TRβ^–/– fetus and excessive for the TRβ^+/– fetus), and reciprocal crosses between TRβ^–/– males and TRβ^+/– females, providing a euiodothyroninemic intrauterine environment. We found that TRβ^–/– dams had reduced litter sizes and pups with lower birth weight but preserved the mendelian TRβ^–/– to TRβ^+/– ratio at birth, indicating that the incongruous TH levels did not decrease intrauterine survival of a specific genotype. The results of studies in newborns demonstrate that TRβ^+/– pups born to TRβ^–/– dams have persistent suppression of serum TSH without a peak. On the other hand, TRβ^–/– pups born to TRβ^+/– dams have lower serum TSH at birth and a tendency to peak higher, compared with TRβ^–/– pups born to TRβ^–/– dams. The studies in the adult progeny demonstrate that TRβ^+/– mice born to TRβ^–/– dams and, thus, exposed to higher intrauterine TH levels, have greater resistance to TH at the level of the pituitary when stimulated with TRH. On the other hand, TRβ^–/– mice born to TRβ^+/– dams and, thus, deprived of TH in uterine life, were more sensitive to TH when similarly stimulated with TRH. Thus, TH exposure in utero has an effect on the regulatory set point of the hypothalamus-pituitary-thyroid axis, which can be seen early in life and persists into adulthood.