Transgenerational epigenetic self-memory of dosage is associated with methylation and altered growth trajectories and neonatal hormones.

Intergenerational and transgenerational epigenetic effects resulting from conditions in previous generations can contribute to environmental adaptation as well as disease susceptibility. Previous studies in rodent and human models have shown that abnormal developmental exposure to thyroid hormone affects endocrine function and thyroid hormone sensitivity in later generations. Since the imprinted type 3 deiodinase gene () regulates sensitivity to thyroid hormones, we hypothesize its epigenetic regulation is altered in descendants of thyroid hormone overexposed individuals. Using DIO3-deficient mice as a model of developmental thyrotoxicosis, we investigated total and allelic expression and growth and endocrine phenotypes in descendants. We observed that male and female developmental overexposure to thyroid hormone altered total and allelic expression in genetically intact descendants in a tissue-specific manner. This was associated with abnormal growth and neonatal levels of thyroid hormone and leptin. Descendant mice also exhibited molecular abnormalities in the imprinted domain, including increased methylation in and altered foetal brain expression of other genes of the imprinted domain. These molecular abnormalities were also observed in the tissues and germ line of DIO3-deficient ancestors originally overexposed to thyroid hormone . Our results provide a novel paradigm of epigenetic self-memory by which gene dosage in a given individual, and its dependent developmental exposure to thyroid hormone, influences its own expression in future generations. This mechanism of epigenetic self-correction of expression in each generation may be instrumental in descendants for their adaptive programming of developmental growth and adult endocrine function.