A Cross-Species Analysis Reveals Dysthyroidism of the Ovaries as a Common Trait of Premature Ovarian Aging

Int J Mol Sci. 2023 Feb 3;24(3):3054. doi: 10.3390/ijms24033054.

Abstract

Although the imbalance of circulating levels of Thyroid Hormones (THs) affects female fertility in vertebrates, its involvement in the promotion of Premature Ovarian Aging (POA) is debated. Therefore, altered synthesis of THs in both thyroid and ovary can be a trait of POA. We investigated the relationship between abnormal TH signaling, dysthyroidism, and POA in evolutionary distant vertebrates: from zebrafish to humans. Ovarian T3 signaling/metabolism was evaluated by measuring T3 levels, T3 responsive transcript, and protein levels along with transcripts governing T3 availability (deiodinases) and signaling (TH receptors) in distinct models of POA depending on genetic background and environmental exposures (e.g., diets, pesticides). Expression levels of well-known (Amh, Gdf9, and Inhibins) and novel (miR143/145 and Gas5) biomarkers of POA were assessed. Ovarian dysthyroidism was slightly influenced by genetics since very few differences were found between C57BL/6J and FVB/NJ females. However, diets exacerbated it in a strain-dependent manner. Similar findings were observed in zebrafish and mouse models of POA induced by developmental and long-life exposure to low-dose chlorpyrifos (CPF). Lastly, the T3 decrease in follicular fluids from women affected by diminished ovarian reserve, as well as of the transcripts modulating T3 signaling/availability in the cumulus cells, confirmed ovarian dysthyroidism as a common and evolutionary conserved trait of POA.

Keywords: chlorpyrifos (CPF); cross-species analysis; diets; ovarian dysthyroidism; premature ovarian aging (POA).

MeSH terms

  • Aging
  • Animals
  • Female
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs* / metabolism
  • Ovary* / metabolism
  • Thyroid Hormones / metabolism
  • Zebrafish / metabolism

Substances

  • Thyroid Hormones
  • MIRN143 microRNA, human
  • MicroRNAs

Grants and funding

This work was supported by: The Italian Workers’ Compensation Authority 571 (grant no 12010), Sensor Regione Campania (grant no 23), Goodwater Regione 572 Campania (POR Campania FESR 2014/2020 O.S. 1.1 Az. 1.1.3 E 1.1.4—CUP 573 B63D18000150007), and POR FESR 2014-2020-Projects (RARE PLATNET, SATIN and 574 COEPICA) Regione Campania.