Effects of maternal levels of thyroid hormone (TH) on the hypothalamus-pituitary-thyroid set point:: Studies in TH receptor β Knockout mice

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) beta(-/-) knockout mouse as a model. We took advantage of the fact that the TR beta-/- females have elevated serum TH but are not thyrotoxic due to resistance to TH. We used crosses between heterozygotes with wild-type phenotype (TR beta+/-) males and TR beta(-/-) females, with a hyperiodothyroninemic (high T-4 and T-3 levels) intrauterine environment (TH congruent with the TR beta(-/-) fetus and excessive for the TR beta(+/-) fetus), and reciprocal crosses between TR beta(-/-) males and TR beta(+/-) females, providing a euiodothyroninemic intrauterine environment. We found that TR beta(-/-) damshad reduced litter sizes and pups with lower birth weight but preserved the mendelian TR beta(-/-) to TR beta(+/-) 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 TR beta(+/-) pups born toTR beta(-/-) dams have persistent suppression of serum TSH without a peak. On the other hand, TR beta(-/-) pups born to TR beta(+/-) dams have lower serum TSH at birth and a tendency to peak higher, compared with TR beta(-/-) pups born to TR beta(-/-) dams. The studies in the adult progeny demonstrate that TR beta(+/-) mice born to TR beta(-/-) 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, TR beta(-/-) mice born to TR beta(+/-) 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 hypothalamuspituitarythyroid axis, which can be seen early in life and persists into adulthood.