Gender-specific effects of dydrogesterone on zebrafish liver metabolism after long-term exposure

Synthetic progestin dydrogesterone is widely used in gynecology and animal husbandry, leading to high environmental detection rates and concentrations. Dydrogesterone influences sex differentiation, gonad development, and spawning in fish. However, its impact on the liver, a vital organ for hormone production and detoxification, remains largely unknown. In this study, zebrafish embryos were exposed to 2.8, 27.6, and 289.8 ng/L of dydrogesterone until they reached sexual maturity. Metabolomics and Fourier transform infrared spectroscopy (FTIR) were employed to investigate alterations in the zebrafish liver. Long-term exposure to dydrogesterone decreased body weight and length in females but increased them in males. The levels of phospholipids, monoglycerides, lysophospholipids, fatty acids, acylcarnitines, acyltaurines, cholesterol, and bile acids increased in the liver of females but decreased in males due to dydrogesterone, making the metabolic pathways the most affected. FTIR analysis revealed a reduction in lipid and protein absorption coupled with an increase in carbohydrate absorption in the liver of exposed males, whereas exposed females exhibited reductions in both lipid and carbohydrate absorption. These findings suggest that long-term exposure to dydrogesterone enhances basic metabolism and physical growth in male zebrafish. To the best of our knowledge, this is the first report on the effects of progestins on body metabolism. Additionally, we find that gender difference is a notable feature of the effects of dydrogesterone on zebrafish.