Study Reveals Epigenetic Changes in Sperm from Non-Genetic Infertility Causes

By Dr. Chinta SidharthanReviewed by Lily Ramsey, LLMJul 3 2024

Epigenetic modifications are those changes in gene expression that occur without alterations in the deoxyribonucleic acid (DNA) sequence but are heritable. Epigenetic changes include modifications to the histone proteins, methylation of DNA, and non-coding ribonucleic acids (RNAs).

Studies have shown that male infertility is linked to epigenetic changes to the sperm brought about by unhealthy lifestyles and chronic conditions such as diabetes and obesity.

A recent review published in Life discusses how non-genetic factors can induce epigenetic modifications to the sperm and cause male infertility.

​​​​​​​Study: Behind the Genetics: The Role of Epigenetics in Infertility-Related Testicular Dysfunction. Image Credit: Peakstock/Shutterstock.com

Background

Research shows that about 15% of male infertility is due to genetic causes, with the prevalence increasing to 25% if cases of azoospermia are included.

Growing evidence from genetic studies has also suggested that mutations in an increasing number of genes are contributing to failure in spermatogenesis. However, recent studies also indicate the role of epigenetic changes in phenotypes of male infertility.

Furthermore, while epigenetic modifications like altered DNA methylation patterns in sperm and histone modifications are linked to oligozoospermia and other infertility factors, non-genetic conditions such as varicocele, chronic diseases like diabetes and obesity, and lifestyle habits such as smoking, alcohol consumption, and medication use have also been associated with male infertility.

The present review examined the known non-genetic factors that cause male infertility related to testicular dysfunction and analyzed the involvement of epigenetic modifications among these factors.

Biological Causes of Infertility

Varicocele is a condition where the enlargement of the veins in the scrotum results in the testicles being depleted of oxygen as large amounts of blood are carried away from them.

It can cause infertility by affecting sperm quality and function. Varicocele has also been associated with epigenetic changes, such as lower methylation patterns in the DNA in the sperm.

Ontological studies have found that the genes showing reduced methylation were involved in the meiotic cell cycle and gamete generation. Repairing varicocele was also found to improve the global DNA methylation patterns in the sperm.

The hypomethylation was believed to be due to increased demethylation activity of the DNA methyl-transferase enzymes 3A and 3B due to the oxidative stress caused by the varicocele.

Another biological factor that is linked to male infertility is obesity, which results in oxidative stress, chronic inflammation, hyperleptinemia, and hyperinsulinemia.

Murine studies have found that a high-fat diet increases the expression of DNA methyl-transferase enzymes in the testicles, causing increased methylation.

Studies among humans have reported differences in methylation patterns in genes involved in sperm cell pluripotency between obese men and men with normal weight.

Chronic prostatitis, which affects close to 9% of men of reproductive age and has a high recurrence rate with age, is also believed to contribute to male infertility.

Prostatitis is associated with changes in sperm parameters, such as lower sperm motility and concentration. However, there is a shortage of studies investigating epigenetic modifications associated with chronic prostatitis, and the only evidence thus far is of protamination ratio changes, potentially contributing to DNA fragmentation in the sperm.

Epigenetic Modifications Due to Lifestyle Factors

The review also examined the impact of lifestyle factors such as smoking, alcohol consumption, diet, stress, and physical activity on male fertility and the epigenetic modifications induced by these lifestyle factors.

Several studies have reported that cigarette smoking impacts DNA methylation and sperm parameters.

Comparisons of non-smoking healthy men with heavy-smoking men with infertility revealed changes in DNA methylation levels in genes coding for protein tyrosine phosphatase receptors, phosphoglycerate mutase family members, and protein tyrosine kinases.

Various studies have also reported significant methylation level differences between smokers and non-smokers and differential expression of numerous other genes that influence sperm parameters.

Alcohol consumption has a dose-dependent association with spermatogenesis damage, and studies have reported that increased alcohol intake can cause hypermethylation in the DNA of the sperm.

Genes with specific imprinting, such as the differentially methylated regions of the G protein subunit alpha S encoding gene, are also affected by methylation changes due to excess alcohol consumption, and these changes have a negative correlation with sperm concentration.

The review also examined the positive impacts of physical activity and essential nutrients on improving male fertility through epigenetic modifications. Folic acid supplementation in the diet increased sperm count in murine models.

Stress was found to significantly lower sperm motility and concentration, with the oxidative stress induced by stress causing changes in histone modifications, DNA methylation, and the expression of non-coding RNAs.

The review also discussed the role of other substance abuse behaviors and exposure to endocrine-disrupting chemicals in inducing epigenetic modifications that contribute to male infertility.

Additionally, the researchers examined the possibility of these epigenetic modifications being inherited by offspring and the long-term health consequences of this transgenerational inheritance.

Conclusions

Overall, through this review, the authors comprehensively examined the various non-genetic factors, such as chronic health conditions and lifestyle habits, that lower male fertility by inducing epigenetic modifications in genes that influence fertility factors.

The study also examined the potential inheritance of these epigenetic modifications and their impact on the health of the offspring. The findings highlight the need to treat these non-genetic conditions and educate patients about lifestyle factors that increase the risk of male infertility.