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 these DNA methylation 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 a larger study 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 the CCDC6 gene. Lower activation of CCDC6 has been linked with preterm birth in previous studies.
Higher methylation near the FNDC5 gene was associated with lower expression of the gene in male placentas but not in female placentas. FNDC5 is 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 as preeclampsia .
Variations in the genes ATP5MG and FAM83A, 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 fetuses grow faster than female fetuses and their pregnancies are more likely to be complicated by such conditions as preeclampsia (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 underlies many pregnancy complications and is thought to set the stage for male and female health differences that occur later in life. Variations in methylation patterns are thought to underlie many of these differences.
The study was conducted by Fasil Tekola-Ayele, Ph.D., of the NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and colleagues at other institutions. It appears in Nature Communications.
Who
Fasil Tekola-Ayele, Ph.D., is available for comment on this study.
Reference
Tekola-Ayele F, et al. Sex-differentiated placental methylation and gene expression regulation has implications for neonatal traits and adult diseases Nature Communications. DOI: https://doi.org/10.1038/s41467-025-58128-3 (2025)
