OR10-5 Reduced Sensitivity to Thyroid Hormone Due to Fetal Exposure to High Thyroid Hormone Levels Is Transmitted along Male Line to Two Subsequent Generations

Exposure of human embryos to high maternal thyroid hormone (TH) concentrations not only affects the newborn but also reduces thyrotroph sensitivity to TH during adult life. Based on results in mice, this latter effect is likely due to induction of the pituitary deiodinase type 3, which accelerates TH inactivation, decreasing therefore the suppression of TSH and resulting in reduced sensitivity to TH (RSTH). As the gene encoding for deiodinase 3 has parent of origin imprinting, we wondered if the effect is transmitted to subsequent generations. We therefore studied the progeny of wild-type (WT) adults (second and third generations), descendent of grandmothers and great grandmothers with high TH levels but euthyroid due to THRB gene mutations, who gave birth to the first WT generation exposed to high TH levels during fetal life. Each subject received 200 µg of thyrotropin-releasing hormone (TRH) iv after 3 days oral treatment with 25 µg liothyronine (L-T3) given twice daily. Blood was collected at intervals over the period of 180 min and analyzed for TSH, prolactin (PRL), sex hormone-binding globulin, ferritin, cholesterol, and creatinine kinase. Post L-T3 treatment, baseline TSH ranged from 0.1-0.5 mU/L and serum T3 levels were elevated but not different among all groups. Following the administration of L-T3, the average TSH peak induced by TRH in the first generation born to mothers with high TH levels was 6.8±1.0 mU/liter compared to 1.6±0.5 mU/liter (P <0.005) of those born to mothers with normal TH levels. There was no overlap in the TSH responses to TRH between the two groups. The second generation consisted of descendants of grandmothers with high TH levels. Their parents were exposed to TH excess but they themselves were not. In this second generation we found that the offspring of fathers, but not of mothers exposed to high TH levels had RSTH as, after L-T3 treatment, they exhibited a peak TSH response to TRH significantly higher, 6.39 ± 0.63 mU/liter compared to 1.58 ± 0.41 mU/liter (P<0.001), respectively. The third generation was comprised of descendants from great grandmothers with high TH levels. Neither their parents nor themselves were exposed to TH excess during their fetal life. Similarly to the second generation, the offspring of fathers, but not of mothers, had RSTH, as evidenced by significantly higher TSH in response to TRH after L-T3 treatment, 4.60 ± 0.61 mU/liter compared to 1.37 ± 0.23 mU/litter (P<001), respectively. No differences were observed in the PRL responses to TRH and in the peripheral markers of TH action listed above. These findings indicate that fetal exposure to high TH levels causes permanent RSTH, which is transmitted by males but not females with RSTH to individuals of both genders in two subsequent generations.