Godschalk Roger W L, Janssen Margit C M, Vanhees Kimberly, van Doorn-Khosrovani Sahar Barjesteh van Waalwijk, van Schooten Frederik-Jan
Department of Pharmacology & Toxicology, School for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, Netherlands.
Front Nutr. 2022 Jul 18;9:904368. doi: 10.3389/fnut.2022.904368. eCollection 2022.
Genistein is a dietary supplement with phyto-estrogenic properties. Therefore, high intake of genistein during pregnancy may have adverse effects on the genetic integrity of testes and germ cells of male offspring. In this study, we examined whether maternal exposure to genistein during pregnancy induced oxidative DNA damage in the male germline at adolescence.
-ΔSRI mice have lower glucose-6-phosphate dehydrogenase (G6PDH) activity, which is important for maintaining levels of reduced glutathione and therefore these mice have an increased susceptibility to oxidative stress. Parental heterozygous -ΔSRI mice received a genistein-rich or control diet, after which they were mated to obtain offspring. During pregnancy, mothers remained on the respective diets and after delivery all animals received control diets. Redox status and oxidative DNA damage were assessed in testes and sperm of 12 weeks old male offspring. Gene expression of , and was assessed in testes, and DNA methylation as possible mechanism for transmission of effects to later life.
Intake of genistein during pregnancy increased oxidative DNA damage in testes of offspring, especially in heterozygous -ΔSRI mice. These increased DNA damage levels coincided with decreased expression of and . Heterozygous -ΔSRI mice had higher levels of DNA strand breaks in sperm compared to wild type littermates, and DNA damage was further enhanced by a genistein-rich maternal diet. G6PDH activity was higher in mice with high maternal intake of genistein compared to control diets, suggesting compensation against oxidative stress. A positive correlation was observed between the levels of DNA methylation and oxidative DNA damage in testes.
These data indicate that prenatal exposure to genistein altered gene expression and increased DNA damage in testes and sperm of adolescent male offspring. These effects of genistein on DNA damage in later life coincided with alterations in DNA methylation.
金雀异黄素是一种具有植物雌激素特性的膳食补充剂。因此，孕期大量摄入金雀异黄素可能会对雄性后代的睾丸和生殖细胞的遗传完整性产生不利影响。在本研究中，我们调查了孕期母体接触金雀异黄素是否会在青春期诱导雄性生殖系中的氧化性DNA损伤。
-ΔSRI小鼠的葡萄糖-6-磷酸脱氢酶（G6PDH）活性较低，这对于维持还原型谷胱甘肽水平很重要，因此这些小鼠对氧化应激的易感性增加。亲代杂合-ΔSRI小鼠接受富含金雀异黄素的饮食或对照饮食，之后进行交配以获得后代。在孕期，母鼠继续食用各自的饮食，分娩后所有动物均接受对照饮食。对12周龄雄性后代的睾丸和精子中的氧化还原状态和氧化性DNA损伤进行评估。在睾丸中评估、和的基因表达，并评估DNA甲基化作为影响传递至后代的可能机制。
孕期摄入金雀异黄素会增加后代睾丸中的氧化性DNA损伤，尤其是在杂合-ΔSRI小鼠中。这些增加的DNA损伤水平与和表达的降低相一致。与野生型同窝小鼠相比，杂合-ΔSRI小鼠精子中的DNA链断裂水平更高，富含金雀异黄素的母体饮食进一步加剧了DNA损伤。与对照饮食相比，母体大量摄入金雀异黄素的小鼠的G6PDH活性更高，表明对氧化应激有补偿作用。在睾丸中观察到DNA甲基化水平与氧化性DNA损伤之间呈正相关。
这些数据表明，产前接触金雀异黄素会改变青春期雄性后代睾丸和精子中的基因表达并增加DNA损伤。金雀异黄素对后期生活中DNA损伤的这些影响与DNA甲基化的改变相一致。
