Overview

• Experiments with cultured cells showed that reducing iron to about 40% of normal levels suppressed Sry gene expression and activated ovarian markers in XY gonadal tissue.
• Administering iron chelators to pregnant mice during the sex determination window led five out of 72 genetically male offspring to develop ovaries or ovotestes.
• Deleting a key iron-accumulation gene in embryonic gonads resulted in ovarian development in seven of 39 XY embryos by increasing Sry repression.
• A prolonged low-iron diet caused male-to-female sex reversal in two of 43 XY pups only when mothers carried a Kdm3a loss-of-function mutation.
• The findings demonstrate that maternal iron levels are crucial for KDM3A-dependent activation of Sry and suggest a broader influence of maternal nutrition on fetal development.