大阪大学Makoto Tachibana团队的最新研究揭示了母体缺铁导致小鼠胚胎雄性向雌性的性别逆转。2025年6月4日，国际知名学术期刊《自然》发表了这一成果。

在这里，该课题组研究了哺乳动物铁代谢、组蛋白去甲基化和性别决定之间的潜在联系。课题组人员发现，在性别决定时期，单主题胚胎性腺中产生Fe²⁺的途径被大量激活。在培养的XY性腺中，铁的螯合降低了KDM3A介导的Sry的H3K9去甲基化水平，大部分消除了Sry的表达，使性腺能够表达卵巢标记物。在体内，胎儿XY性腺体细胞中铁结合所需的Tfrc基因的条件缺失，或妊娠小鼠体内可利用铁的急性药物抑制，导致一定比例的后代出现雄性到雌性的性腺性别逆转，突出了铁代谢在雄性性别决定中的关键作用。最后，长期给怀孕小鼠喂食低铁饮食，并结合KDM3A杂合子变体（本身没有观察到的影响），抑制Sry表达，并在一些后代中引起雄性向雌性的性别逆转，揭示了母体饮食铁与胎儿发育结局之间的联系。

据介绍，铁（Fe²⁺）是所有真核细胞中各种氧化还原酶反应所必需的，包括DNA和蛋白质的去甲基化。在雄性性腺发育过程中，组蛋白去甲基化是y染色体性别决定基因Sry正常表观遗传调控所必需的。

附：英文原文

Title: Maternal iron deficiency causes male-to-female sex reversal in mouse embryos

Author: Okashita, Naoki, Maeda, Ryo, Kuroki, Shunsuke, Sasaki, Kyona, Uno, Yoko, Koopman, Peter, Tachibana, Makoto

Issue&Volume: 2025-06-04

Abstract: Ferrous iron (Fe2+) is essential in all eukaryotic cells for various oxidoreductase reactions, including the demethylation of DNA and proteins. Histone demethylation is required for normal epigenetic regulation of the Y-chromosomal sex-determining gene Sry in developing gonads during male sex determination1,2. Here we investigate the potential connection between iron metabolism, histone demethylation and sex determination in mammals. We found that Fe2+-producing pathways are substantially activated in mouse embryonic gonads during the sex-determining period. Chelation of iron in cultured XY gonads reduced the level of KDM3A-mediated H3K9 demethylation of Sry, mostly abolished Sry expression and caused the gonads to express ovarian markers. In vivo, conditional deletion of the gene Tfrc—which is required for iron incorporation—in fetal XY gonadal somatic cells, or acute pharmaceutical suppression of available iron in pregnant mice, resulted in male-to-female gonadal sex reversal in a proportion of offspring, highlighting the pivotal role of iron metabolism in male sex determination. Finally, long-term feeding of pregnant mice with a low-iron diet, when combined with a heterozygous variant of Kdm3a that by itself has no observable effect, suppressed Sry expression and caused male-to-female sex reversal in some of the progeny, revealing a connection between maternal dietary iron and fetal developmental outcomes.

DOI: 10.1038/s41586-025-09063-2

Source: https://www.nature.com/articles/s41586-025-09063-2