PLMI Blog

Identifying variations in genetic and biological processes can pave the way for improved and individualized fertility outcomes. Epigenetics describes how these mechanisms are shaped by nutrition, lifestyle, and environmental factors, which play pivotal roles in fertility. A growing body of evidence suggests that nutrition across the entire lifespan exerts a powerful influence in improving processes in the body related to fertility. A recent extensive review and meta-analysis of the literature describes and underscores these relationships (1).

The Power of Epigenetics

Epigenetic mechanisms have been proven to play a significant role in infertility. The term “epigenome” originates from the word “epi,” or “above” the genome, and it comprises compounds that modify the genome.

Despite there being over 200 different cell types in the human body, each type contains the same genetic information (1). Various cells carry distinct epigenetic marks, inherited from cell division and can pass from one generation to the next, independently of their DNA sequence. These chemical marks play an integral role in modulating cellular functions that influence genetic expression.

Genomics

Single gene disorders account for a percentage of infertility cases, with recent focus on single nucleotide polymorphisms (SNPs) correlated to fertility-related conditions. Often, underlying infertility causes are multifaceted and not explained by single gene disorders (2). Single nucleotide polymorphisms (SNPs) have been identified as contributors and confounding factors to conditions that cause infertility.

Female Fertility

Research findings indicate that epigenetic variations contribute to gene dysregulation and compromised health status. Abnormal expressions of the HOXA10 gene have been found to play crucial roles in the pathophysiology of endometriosis, which can affect fertility (3). HOXA10 is a key regulatory gene in the DNA-binding transcription factor family, modulating important processes relative to fertility (1).

Studies have demonstrated abnormalities in the growth-regulating HOXA10 gene in females with endometriosis. In healthy, fertile women, HOXA10 gene expression is cyclic, peaking during the mid-secretory phase, coinciding with embryo implantation, histological differentiation, and increased systemic estrogen and progesterone levels. Adequate levels of HOXA10 expression in the endometrium are imperative for decidual transformation, a process that results in vast alterations of cells during embryo implantation in preparation for pregnancy. There is evidence that dysregulation or defects in HOXA10 expression may contribute to recurrent miscarriages and infertility by impeding these processes.

Female infertility is also suggested to stem from conditions such as PCOS, endometriosis, and unexplained infertility. PCOS is a leading cause influenced by genetic predispositions, as well as epigenetic and developmental factors. Hormonal and metabolic disruptions can further increase susceptibility to PCOS. Understanding epigenetic mechanisms, hence, is crucial in comprehending the complexities of impeded fertility (3-5).

Male Fertility

The Role of RNA – Research has increasingly focused on understanding the roles of RNA molecules derived from sperm, encompassing both coding and non-coding roles. While sperm are transcriptionally inactive, they contain various essential RNA types (mRNA and non-coding RNA) that have significant roles in epigenetic inheritance, development, and spermatogenesis. Studies comparing sperm RNA profiles in a number of male fertility conditions reveal diverse RNA profiles, highlighting their potential relevance to paternal fertility.

Environmental factors, including toxicants, are implicated in testicular diseases and may impact epigenetic inheritance through sperm epigenome and transcriptome factors affecting early embryonic stem cells. Research also links long-term infertility to alterations in methylation patterns, particularly in genomic imprinting regions (1, 3, 6, 7).

Sperm Chromatin Reorganization – Sperm chromatin undergoes significant reorganization during spermatogenesis, where histones are largely replaced by protamines, compacting DNA while reducing vulnerability to environmental factors. This process ensures sperm nuclei become highly condensed, promoting increased motility and protecting the genome from degradation and oxidative damage within the female reproductive tract. The replacement of histones with transitional proteins and then with protamines facilitates this condensation, which is integral for sperm function (1).

Histone Alterations – Modifications to histones can favorably or negatively affect the binding of regulatory factors to DNA, thereby influencing activity of genes and their expression. Acetylation of H3 and H4, methylation of H3K4, and ubiquitination, a form of post-translational modification of H2B, often enhance genetic expression in testicular tissue. Conversely, methylation of H3K27 and H3K9, and ubiquitination of H2A, have been shown to silence gene expression. Both H3K4 and H3K27 methylation have been implicated in activating and inactivating gene expression processes.

Histone retention in imprinted gene clusters and alterations in protamines and residual histones

may contribute to male infertility. Research involving 291 Assisted Reproductive Technology (ART) cycles underscores the relevance of the histone-protamine ratio (HPR) in embryonic development and ART success rates. Higher HPR levels correlated with significantly increased blastocyst formation rates compared to lower HPR levels. Therefore, optimizing HPR may improve embryo development in ART settings (1).

DNA Methylation

DNA methylation is a significant epigenetic marker frequently studied for its role in the development of gametes in both men and women (1).

Genes frequently associated with male infertility often exhibit abnormalities in DNA methylation, particularly in imprinted genes (MEST and H19) and non-imprinted genes (MTHFR). Methylation plays a strong role in the expression of imprinted genes, influencing whether the allele originates from the maternal or paternal side. Following fertilization, demethylation of maternal and paternal alleles occurs, yet imprinted genes maintain methyl marks distinctive to their parental origin (1).

DNMT1, a gene that provides instructions for the enzyme DNA methyltransferase, is essential for maintaining DNA methylation during DNA replication. The absence of this gene often results in abnormalities in spermatogenesis and a loss of methylation, primarily in paternal imprinted genes. DNMT enzymes are integral for DNA methylation and adequate spermatogenesis. Deficiency can disrupt spermatogenesis and may result in impeded methylation of paternal imprinted genes (1, 8).

Age, Environment & Lifestyle

Infertility rates can be influenced by factors such as age, environment, lifestyle, and overall health. While 80% of infertility cases are associated with conditions like endometriosis or PCOS, the remaining 20% have no clear cause. Hormonal and metabolic disturbances from environmental factors can create (epi)genetic susceptibility to PCOS, by influencing the development and clinical outcomes of the condition (9). Poor diet, chronic stress, inadequate sleep, and substance use can further compound processes in the body important for fertility.

Western Diet & Infertility

The Western diet, prevalent in developed countries, is characterized by high consumption of simple carbohydrates, saturated and trans fats, and animal protein, with reduced levels of phytonutrients, fiber, and unsaturated fats. This pattern of eating has been linked to an increased risk of infertility. Notably, the quality of semen has been shown to be reduced with increased adaptation of the Western diet (10). Processed meats, high saturated fat dairy products, alcohol consumption, and refined carbohydrates, coupled with a lack of vegetables, fruits, seafood, nuts, poultry, and whole grains, may negatively impact semen quality and reduce fertility, as evidenced in various studies (11-13).

Phytoestrogens

Phytoestrogens, plant-derived compounds with estrogen-like properties that bind to estrogen receptors, have been suggested to influence gene expression once transported into the nucleus from the cytoplasm. However, research results appear to be mixed. Studies initially suggested a potential negative impact on sperm count and fertility with regular soy consumption (containing high amounts of phytoestrogens). However, more recent findings suggest that these products may not adversely affect fertility and could potentially enhance outcomes in ARTs due to their antimutagenic and antioxidant properties. Further research is warranted to fully understand the effects of phytoestrogens, particularly isoflavones, on fertility (14, 15).

NUTRITION SUPPORT FOR IMPROVED FERTILITY

Epigenetic mechanisms influencing fertility can be impacted by nutrition, as well as aging and environmental factors. Consumption of omega-3 fatty acids and various nutrients, including vitamins B6, C, D, B12, biotin, folate, choline, iron, selenium, iodine zinc, and resveratrol may positively affect fertility treatments as they are integral for fetal development and reproductive health, as evidenced by a growing body of research (16). However, excess and deficiency of these trace elements can lead to adverse pregnancy outcomes and infertility in women (1). Sufficient intake of these nutrients has been suggested to improve fertility outcomes (1).

Antioxidants – Vitamins A, C, and E support maintaining an antioxidant–prooxidant balance while protecting sperm DNA from oxidative damage and improving count and motility. Further antioxidants associated with improved fertility include selenium, glutathione, coenzyme Q10, carnitine, and lycopene. These help counteract free radicals (ROS) and have been shown to be positively associated with fertility (17).

Selenium deficiency has been linked to reproductive disorders, as it reduces ROS production in sperm and increases glutathione activity. Supplementing infertile men with 400 IU of vitamin E and 200 μg of selenium daily for 100 days led to a 52.6% improvement in sperm motility and morphology (18).

One study found that administering antioxidants to children conceived through IVF improved nitric oxide (NO) bioavailability and vascular response in both systemic and pulmonary circulation (19).

Vitamin C supplementation has also been demonstrated to have a positive impact on stress-induced infertility due to its testosterone-increasing and antioxidant effects. These findings also showed that a high dose of vitamin C supplementation increased testosterone levels by favorably affecting the hypothalamus–pituitary–testis axis (20).

Vitamin D – Vitamin D receptors are found in the ovaries, uterus, endometrium, and placenta. Vitamin D may influence infertility by reducing levels of interleukin-6 (IL-6), a pro-inflammatory cytokine. One study demonstrated that women with low vitamin D and elevated IL-6 levels had a 10.6 times higher risk of infertility (21). Inflammatory factors, such as L-6, have been shown to be highly correlated with infertility in individuals with endometriosis (22).

Research has also demonstrated a correlation between the quality of semen and serum vitamin D levels in men. Vitamin D receptors have been demonstrated to be lower in infertility (23). Low serum vitamin D has been associated with reduced sperm count, as well as alterations in sperm motility and morphology (24).

Zinc – Inadequate zinc intake has been shown to reduce antioxidant defenses and increase oxidative damage in sperm cells. For men with oligospermia, a condition characterized by reduced sperm count, zinc supplementation was demonstrated to improve motility, morphology, and count (25).

A systematic review and meta-analysis found links between paternal folate status and sperm quality, fertility, congenital malformations, and placental weight. This underscores that a poor paternal or maternal diet can impact the epigenetic marks of offspring, potentially leading to infertility (25). Zinc has also been implicated to have gut, hormonal, and neurotransmitter modulating roles, further highlighting its role in improved fertility.

A Note About Assisted Reproductive Techniques (ARTs)

Treatments addressing the genetics and epigenetics of infertility include assisted reproductive techniques (ARTs) such as IVF. While these techniques may improve chances of fertility, they also have been found to come with increased risks of complications that include hypertension, placental issues, gestational diabetes, preterm birth, and low birth weight.

Conditions such as PCOS, endometriosis, and placental dysfunction contribute significantly to maternal infertility, affecting placentation and implantation. Genetic and epigenetic factors, along with environmental impacts from fertility treatments, contribute to these complications, with recent research implicating the role of SNPs and the potential benefits of antioxidant treatments in improving vascular function in children conceived through IVF (3).

Epigenetic modifications, including DNA methylation and non-coding RNA regulation, impact patterns of gene expression significant for development and long-term health implications. Understanding these complex factors is essential for optimizing infertility treatments and enhancing outcomes (1).

Personalized Medicine

The epigenome modulates the expression of genes, with modifications occurring in embryonic development and throughout the lifespan. This journey involves continuous and vast transformations in response to our genetic makeup, lifestyle, environment, and diet. Advances in sequencing technologies such as proteomics (study of RNA), genomics, and metabolomics can pinpoint underlying mechanisms involved in the complexity of impeded fertility based on biological and environmental factors, yielding more efficient treatment modalities.

Join us on July 30th, from 5 to 7 pm PST, for this free webinar, The Importance of Lifestyle Genetics in Healthy Aging: Relevance of Genetics from Preconception Across the Lifespan. Experts Denise Furness, PhD, Leslie P. Stone, MD, IFMCP, and Jeffrey Bland, PhD, will discuss genomic-focused, bio-individualized interventions for addressing applications of genetic analysis, providing novel insights into improving health across the lifespan.

References:

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