Intergenerational effects of paternal thyroid hormones on female fertility
Document Type
Event
Faculty Mentor
Arturo Hernandez
Abstract
Background: Familial studies show high heritability of complex human conditions, yet genetic variation accounts for less than 15% of this heritability. Infertility is approximately 50% heritable in both sexes, suggesting that environmentally induced epigenetic mechanisms contribute to its etiology. We use a Dio3KO mouse model of in utero thyroid hormone overexposure to examine effects on disease‑relevant phenotypes in exposed offspring and their descendants. Preliminary observations in the lab indicated that heterozygous females born to overexposed fathers failed to produce litters when mated with genetically normal males, while heterozygous females from non-exposed fathers all produced litters within a month. Hypothesis: Females generated by fathers overexposed to thyroid hormone during development exhibit molecular abnormalities in the hypothalamic–pituitary–gonadal axis that affect reproductive function. Experimental design: We studied three groups of CD‑1 females aged approximately 4 months: heterozygous females with exposed fathers (Het‑EF, n=3), heterozygous females with non‑exposed fathers (Het‑NEF, n=6), and wild‑type females with wild‑type fathers (WT, n=8). Reproductive and endocrine‑relevant tissues (adrenal glands, ovaries, uterine horns, pituitary, hypothalamus) were collected, along with liver and blood for future hormonal analysis. Estrous cyclicity was assessed in an additional cohort of Het‑EF (n=6) and WT (n=6) females, including WT females on a C57BL/6J background. Methods: qPCR quantified mRNA expression of genes regulating the reproductive axis, steroid hormone biosynthesis, and thyroid hormone responsiveness. Estrous cycles were evaluated daily for four weeks by microscopic examination of vaginal smears. Statistical analyses used one‑way ANOVA with Tukey’s post hoc test (P<0.05). Results: Relative to WT and Het‑NEF controls, Het‑EF females showed significantly increased ovarian expression of steroidogenic genes Star, Cyp11a1, and Cyp11b1. In adrenal glands, Het‑EF females exhibited decreased expression of Cyp21a1 and the thyroid hormone–regulated gene Dio3os. Ongoing analyses suggest lengthened estrous cycles in Het‑EF females. Conclusion: These findings indicate that paternal thyroid hormone excess disrupts the reproductive endocrine axis in female offspring and highlight a potential role for paternal endocrine environment in shaping female reproductive function and contributing to the missing heritability of female infertility.
Intergenerational effects of paternal thyroid hormones on female fertility
Background: Familial studies show high heritability of complex human conditions, yet genetic variation accounts for less than 15% of this heritability. Infertility is approximately 50% heritable in both sexes, suggesting that environmentally induced epigenetic mechanisms contribute to its etiology. We use a Dio3KO mouse model of in utero thyroid hormone overexposure to examine effects on disease‑relevant phenotypes in exposed offspring and their descendants. Preliminary observations in the lab indicated that heterozygous females born to overexposed fathers failed to produce litters when mated with genetically normal males, while heterozygous females from non-exposed fathers all produced litters within a month. Hypothesis: Females generated by fathers overexposed to thyroid hormone during development exhibit molecular abnormalities in the hypothalamic–pituitary–gonadal axis that affect reproductive function. Experimental design: We studied three groups of CD‑1 females aged approximately 4 months: heterozygous females with exposed fathers (Het‑EF, n=3), heterozygous females with non‑exposed fathers (Het‑NEF, n=6), and wild‑type females with wild‑type fathers (WT, n=8). Reproductive and endocrine‑relevant tissues (adrenal glands, ovaries, uterine horns, pituitary, hypothalamus) were collected, along with liver and blood for future hormonal analysis. Estrous cyclicity was assessed in an additional cohort of Het‑EF (n=6) and WT (n=6) females, including WT females on a C57BL/6J background. Methods: qPCR quantified mRNA expression of genes regulating the reproductive axis, steroid hormone biosynthesis, and thyroid hormone responsiveness. Estrous cycles were evaluated daily for four weeks by microscopic examination of vaginal smears. Statistical analyses used one‑way ANOVA with Tukey’s post hoc test (P<0.05). Results: Relative to WT and Het‑NEF controls, Het‑EF females showed significantly increased ovarian expression of steroidogenic genes Star, Cyp11a1, and Cyp11b1. In adrenal glands, Het‑EF females exhibited decreased expression of Cyp21a1 and the thyroid hormone–regulated gene Dio3os. Ongoing analyses suggest lengthened estrous cycles in Het‑EF females. Conclusion: These findings indicate that paternal thyroid hormone excess disrupts the reproductive endocrine axis in female offspring and highlight a potential role for paternal endocrine environment in shaping female reproductive function and contributing to the missing heritability of female infertility.
