Epigenetic differences identified between placentas of male and female fetuses

[mensfe_admin]

by Dr Marisa Flook

Methylation in the placentas of male and female fetuses has marked differences, according to a study by researchers at the National Institutes of Health, Bethesda, Maryland.

DNA methylation is an epigenetic mechanism that cells use to control gene expression. It occurs when a tag known as a methyl group is added to the DNA molecule without altering its underlying sequence. The addition of this tag allows the regulation of gene expression by turning genes 'on' or 'off'. Using multi-omics techniques, to determine the precise molecular changes which define cell types and their development, the researchers analysed the methylation patterns of 152 male and 149 female placental samples from a larger study. The placenta develops from cells that are part of the early embryo, and the researchers have identified differences between male and female placentas that may play a role in birthweight and adult diseases.

Publishing their findings in Nature Communications the authors wrote: 'This study offered several unique insights about the landscape of sex differences in the level and genetic regulation of methylation and gene expression in the human placenta... [The] findings suggest the potential role of placenta-mediated sex differences in developmental and later-life physiological traits and diseases.'

The researchers identified 6077 DNA sites with different methylation patterns between males and females, of which 2497 were previously unreported. Overall, 66.9 percent had higher methylation in DNA from male placentas, which were linked with greater neonatal size. The remaining 33.1 percent had higher methylation in DNA from female placentas and were linked to greater placental size.

Some increases in methylation were sex specific, such as DNA sites near the CCDC6 gene in males and the NIRF1 gene in females. Reduced expression of these genes has been previously linked to preterm deliveries and preeclampsia, respectively.

The authors found that 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 in the production of irisin, which protects the placenta from damage by reactive oxygen molecules and insulin resistance. Lower irisin levels have been associated with preeclampsia and lower placental weight.

Additionally, the researchers identified variations in the ATP5MG and FAM83A genes expressed in the female placenta that have been associated with asthma, hay fever, eczema and breast cancer.

The authors noted that their study was unable to distinguish sex differences that emerged in early gestation from those that emerged in later gestation. For example, a previous methylation study on first trimester placentas found that ZNF300 was highly methylated in male but not female placentas (see BioNews 1262), which was similarly observed in the present study.

Dysfunction of the placenta underlies many pregnancy complications and is thought to determine male and female health differences that occur later in life. The differences in DNA methylation uncovered in this study could support future research on the higher risk for pregnancy complications involving male fetuses, such as stillbirth and prematurity.

Temperature controls mechanism in sperm linked to male fertility
by Dr Coco Newton

The mobility of sperm appears to be temperature-dependent due to the action of a single protein, according to research carried out in mice.

Researchers from Washington University School of Medicine, St Louis, Missouri used techniques originally developed to study brain cells to show that electrical discharges from a particular sperm protein, CatSper, increased when the temperature surrounding the cell surpassed 38 degrees Celsius. In parallel, sperm behaviour switched from a smooth swim-like motion used for navigation to hyperactive propellor movements needed for entry into the egg.

'That hyperactive state in sperm is key for successful fertilisation, and no one knew exactly how temperature triggers it,' said professor of cell biology and physiology Polina Lishko, corresponding author of the paper published in the journal Nature Communications.

Previous research suggested sperm mobility changes may be activated by environment pH or reproductive hormones like progesterone (see BioNews 1078, 1102 and 1121).

While the study was done in mice, the CatSper protein is common to all mammals, and previous research has linked mutations in the CatSper gene to human male infertility. The protein regulates calcium ion entry into sperm cells, thereby controlling the sperm tail motion.

Because most mammals – including humans – create and store sperm in testes around two to four degrees lower than the body temperature, the researchers hypothesised that reaching the warmer internal female reproductive tract might activate CatSper.

Professor Lishko suggested the findings may offer new approaches to male contraception and infertility treatments, with previous attempts to target the protein proving unsuccessful: 'Instead of creating inhibitors, it might be possible to activate CatSper with temperature, thus prematurely switching on this channel to drain the sperm of energy, so that by the time the sperm cell is ready to do its job and enter the egg cell, it is powerless.'

The study also revealed that the pH of the testes and an additional ejaculate molecule, spermine, both appear to shield CatSper from warmer temperatures to prevent sperm activating before reaching the egg.

The authors drew on evolutionary observations that species without the CatSper proteins, such as birds, have internal testes where temperature-activation is redundant. They also highlighted that men with varicocele – an overgrowth of blood vessels leading to increased testicular temperature – show impaired sperm motility which can lead to infertility. However, whether CatSper is the mechanism by which variocele affects fertility remains unknown