IJMS, Vol. 26, Pages 11807: 17β-Estradiol and Its Metabolites Induce Oxidative Damage to Membrane Lipids in Primary Porcine Thyroid Follicular Cells—Comparison Between Sexes

International Journal of Molecular Sciences doi: 10.3390/ijms262411807

Authors:
Jan Stępniak
Małgorzata Karbownik-Lewińska

Sexual dimorphism significantly influences the epidemiology of thyroid disorders, with females exhibiting higher incidence of thyroid diseases. Estrogens and their hydroxylated metabolites are key regulators of cellular redox balance and may contribute to sex-specific susceptibility through pro-oxidative mechanisms. However, the impact of individual estrogen metabolites on oxidative stress in thyroid follicular cells remains poorly defined. Here, we investigated the pro-oxidative effects of 17β-estradiol (E2) and its hydroxylated metabolites—2-hydroxyestradiol (2-OHE2), 4-hydroxyestradiol (4-OHE2), and 16α-hydroxyestrone (16α-OHE1)—in primary porcine thyroid cell cultures from males and females. Primary follicular thyroid cells were isolated from six male and six female pigs. Cells were exposed to E2 (100 nM) or its metabolites (1 μM), with or without Fenton reaction substrates (Fe2+ and H2O2), for 24 h. Lipid peroxidation (an index of oxidative damage to lipids) was quantified using BODIPY® 581/591 C11 fluorescence via flow cytometry. Basal lipid peroxidation did not differ between sexes. 2-OHE2 increased lipid peroxidation in both male and female thyroid cells, with a more pronounced effect observed in males. In contrast, 4-OHE2 selectively enhanced lipid peroxidation only in female cells. 16α-OHE1 elevated lipid peroxidation in both sexes. E2 significantly increased lipid peroxidation in both male and female cells. Among all compounds tested, E2 exhibited the most potent pro-oxidative activity, particularly in female-derived cells. These findings provide novel insights into the redox-modulating effects of estrogen metabolism in the thyroid and suggest a potential molecular basis for sex-related susceptibility to thyroid dysfunction. While based on an in vitro porcine model, the study increases our understanding of the mechanisms by which estrogenic compounds may influence thyroid pathophysiology, possibly including early events in thyroid disease development or oncogenesis.

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