Reduced Sensitivity to Thyroid Hormone as a Transgenerational Epigenetic Marker Transmitted Along Human Male Line.

BACKGROUND: Evidence for transgenerational epigenetic inheritance in humans is still controversial given the requirement to demonstrate persistence of the phenotype across three generations. In a previous study we showed that exposure of human and mouse embryos to high maternal thyroid hormone (TH) concentrations not only affects the newborns but also subsequently reduces thyrotroph sensitivity to TH during adult life. In the current investigation we setout to determine if this epigenetic effect is transmitted by humans not exposed in utero to high TH levels to their offspring.

METHODS: We took advantage of the high frequency of intrauterine exposure to high TH in the Azorean wild-type population born to healthy mothers with high TH levels owing to a heterozygous TH receptor beta gene mutation. We studied wide-type individuals from F2 (second) and F3 (third) generations, whose parents and grandparents, respectively, were not exposed to high maternal TH levels. 26 individuals belonging to 17 nuclear families were tested for their sensitivity to TH using their TSH response to TRH after administration of L-T3.

RESULTS: We found preservation of reduced sensitivity to TH (RSTH) in descendants of males but not of females with likewise RSTH. In F2, offspring of fathers, but not of mothers exposed to high TH levels had RSTH [TRH-stimulated TSH of 6.39 ± 0.63 vs 1.58 ± 0.41 mU/L (P<0.001), respectively, after treatment with L-T3]. In F3, whose parents nor themselves were exposed to TH excess during their fetal life, descendants of fathers and not mothers had RSTH [TRH-stimulated TSH of 4.60 ± 0.61 vs 1.37 ± 0.23 mU/litter (P<0.01), respectively, after pretreatment with L-T3].

CONCLUSIONS: Since intrauterine total body and gonadal exposure to elevated TH can potentially affect only the F1 and F2, respectively, the results obtained from F3 confirm a true inheritance of an epigenetic effect, scarcely observed in humans. While the exact mechanism underlying the inheritance of this epigenetic effect remains unknown, it correlates with type 3 deiodinase overexpression demonstrated in pituitary glands of mice born to dams with high TH. This enzyme inactivates TH, and is encoded by an imprinted gene with specific parent of origin expression.