Iron deficiency in mothers silences key sex gene, causes male-to-female reversal in mice

Yahoo

2 days ago

Scientists in Japan and Australia have shown that iron deficiency during pregnancy can cause a complete sex reversal in genetically male mice carrying XY chromosomes, leading them to develop ovaries.
The research team from Japan's Osaka University and Australia's University of Queensland found that a severe lack of iron in the womb caused some genetically male embryos to exhibit female traits in addition to forming female reproductive glands.
The findings challenge conventional theories by providing the first evidence in mammals that an environmental factor, rather than genes alone, can influence the biological process of sex determination.
According to the researchers, the results show that the developmental path, which was based on the assumption that a mammal's sex is determined at conception by the presence of XY (male) or XX (female) chromosomes, is not as fixed as widely believed.
Led by Makoto Tachibana, PhD, a biology professor at Osaka University, the research team revealed that the SRY gene, found on the Y chromosome, plays a central role in sexual differentiation in mammals.
If this genetic fragment is present, the gonads, which are the primary glands responsible for producing reproductive cells, begin forming testes around six weeks into development. In its absence, they naturally develop into ovaries.
However, the researchers found that when iron concentration was reduced by 60 percent at the cellular level, it interfered with sex differentiation by silencing the SRY gene at a critical stage of development.
During mice trails, the team discovered that 6 out of 39 genetically male (XY) mice born to iron-deficient mothers developed fully formed ovaries. Another individual was intersex, with one ovary and one testicle.
Similar outcomes were observed in additional experiments where mothers were given a drug that removes iron from the body, further confirming the role of iron levels in sex development. In this case, five out of 72 genetically male embryos developed female sex organs.
"No dietary influences on sex development have ever been established scientifically before," Peter Koopman, PhD, an emeritus professor at the University of Queensland said.
According to the researchers, the process seems to rely on epigenetics, which are chemical alterations to DNA that influence how genes are expressed without altering the genetic code itself. Simply put, this field of research explores how behavior and environment can cause changes that affect the way genes work.
In he current case, iron deficiency affected an enzyme called Lysine demethylase 3A (also known as KDM3A), which helps activate the SRY gene. Without adequate iron, the enzyme cannot function properly, leading to the gene being switched off.
Even though the findings are limited to mice and the effects on human pregnancies were not studied, Koopman emphasized that the implications could reach much further.
"Iron deficiency affects an estimated 40 percent of pregnant women, and iron has not been previously suspected of influencing sex determination in the embryo," the professor said in a press release.
"It is possible the results mean that the potential for sex reversal may be a concern to a subset of pregnant women who are already predisposed in some way to iron deficiency," he concluded.
The researchers now hope to explore whether similar mechanisms exist in humans, and under what conditions iron levels could influence early fetal development.
The study has been published in the journal Nature.