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

IF 50.5 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES
Nature Pub Date : 2025-06-04 DOI:10.1038/s41586-025-09063-2
Naoki Okashita, Ryo Maeda, Shunsuke Kuroki, Kyona Sasaki, Yoko Uno, Peter Koopman, Makoto Tachibana
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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.

Abstract Image

母体缺铁导致小鼠胚胎雄性向雌性的性别逆转
亚铁(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1,2。在这里,我们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。我们发现,在小鼠胚胎性腺中,Fe2+的产生途径在性别决定期间被大量激活。在培养的XY性腺中,铁螯合降低了kdm3a介导的Sry的H3K9去甲基化水平,大部分消除了Sry的表达,并导致性腺表达卵巢标志物。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杂合变体(其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。
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来源期刊
Nature
Nature 综合性期刊-综合性期刊
CiteScore
90.00
自引率
1.20%
发文量
3652
审稿时长
3 months
期刊介绍: Nature is a prestigious international journal that publishes peer-reviewed research in various scientific and technological fields. The selection of articles is based on criteria such as originality, importance, interdisciplinary relevance, timeliness, accessibility, elegance, and surprising conclusions. In addition to showcasing significant scientific advances, Nature delivers rapid, authoritative, insightful news, and interpretation of current and upcoming trends impacting science, scientists, and the broader public. The journal serves a dual purpose: firstly, to promptly share noteworthy scientific advances and foster discussions among scientists, and secondly, to ensure the swift dissemination of scientific results globally, emphasizing their significance for knowledge, culture, and daily life.
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