Media AdvisoryThursday, May 1, 2025
NIH findings may lead to insights on pregnancy complications, adult health.
The genes of male and female placentas have marked differences in how they are expressed, according to a study by researchers at the National Institutes of Health (NIH) and other institutions. These differences involve the presence or absence of tags on DNA known as methyl groups, which switch genes on or off without changing their structure. Understanding theseDNA methylation(link is external)patterns may inform future research on the higher risk for pregnancy complications involving male fetuses, such as stillbirth and prematurity, as well as later life health conditions that occur in adults who were born after a complicated pregnancy.
Researchers analyzed male and female placental samples from alarger study(link is external)for differences in their methylation patterns, and found differences in gene activity between male and female placentas that may play a role in birthweight and adult diseases.
The study identified 2,497 previously unreported DNA sites that had different methylation patterns for males and females. Of these and more than 2,500 sites that had also been identified by previous studies, 66.9% of large increases in methylation occurred in DNA from male placentas and 33.1% from female placentas. Increases in methylation in male placentas was linked with greater neonatal size whereas those in females was linked with greater placental size.
Some increases in methylation found in male placentas were located near theCCDC6gene. Lower activation ofCCDC6has been linked with preterm birth in previous studies.
Higher methylation near theFNDC5gene was associated with lower expression of the gene in male placentas but not in female placentas.FNDC5is involved with the manufacture of irisin, which protects the placenta from damage by reactive oxygen molecules and insulin resistance (cells’ difficulty in using insulin to lower blood sugar.) Lower irisin levels have been associated with the pregnancy-related high blood pressure disorder, known aspreeclampsia(link is external).
Variations in the genesATP5MGandFAM83A,expressed in female placentas, have been associated with asthma, hay fever, eczema (dry, itchy, inflamed skin) and higher risk for breast cancer later in life.
Genetic factors influence the health differences between males and females, from before birth to later in life. Male fetusesgrow faster(link is external)than female fetuses and their pregnancies are more likely to becomplicated by(link is external)such conditions aspreeclampsia(link is external)(a hypertensive disorder of pregnancy), failure to grow at an adequate rate, and preterm birth. They also are more likely to die in the year after birth.Dysfunction of the placenta(link is external)underlies many pregnancy complications and is thought to set the stage for male and female health differences that occur later in life. Variations inmethylation patterns(link is external)are thought to underlie many of these differences.
The study was conducted by Fasil Tekola-Ayele, Ph.D., of the NIH’sEunice Kennedy ShriverNational Institute of Child Health and Human Development (NICHD) and colleagues at other institutions. It appears inNature Communications.
Fasil Tekola-Ayele, Ph.D., is available for comment on this study.
Tekola-Ayele F,et al. Sex-differentiated placental methylation and gene expression regulation has implications for neonatal traits and adult diseasesNature Communications.DOI:https://doi.org/10.1038/s41467-025-58128-3(link is external)(2025)
About the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): NICHD leads research and training to understand human development, improve reproductive health, enhance the lives of children and adolescents, and optimize abilities for all. For more information, visithttps://www.nichd.nih.gov(link is external).
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