Epigenetic Transgenerational Actions of Endocrine Disruptors and Male Fertility
Written by Ben Bunting: BA(Hons), PGCert.
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There is growing evidence of a link between endocrine disruptors and male fertility. In a recent study, Yuan et al. found that dibutyl phthalate significantly reduced the number of sperm and Sertoli cells in male rats, and decreased serum testosterone levels. Changes in male reproductive function were associated with distinct changes in DNA methylation, including hypomethylation of the promoter of the Fstl3 gene. Metabolic analysis of exposed rats revealed increased levels of betaine and a decreased betaine homocysteine S-methyltransferase, suggesting a disruption of the methionine cycle.
DNMTs
The mechanisms of DNMTs' transgenerational actions on human sperm and testes are unclear. Some researchers think that the first effects of TCDD exposure may be mediated by alterations in normal methyltransferase activity. Others speculate that a different mechanism may be involved. This article reviews some possible mechanisms.
In this study, we aimed to understand the mechanisms of DNMTs-induced effects on the sperm's epigenome. We used vinclozolin, an endocrine disruptor, which has transgenerational effects on sperm's development and adult-onset disease states. We found that vinclozolin's transgenerational actions on the testis resulted in reproducible changes in gene expression, with most genes being silenced or reduced. Moreover, we observed dramatic changes in methyltransferases (Dnmt3A and Dnmt3L) in the F1 and F2 vinclozolin-treated testis.
The results suggest that exposure to endocrine disruptors to DNMTs affects sperm vulnerability, although most studies involve animal models. Some studies, however, show that exposure to certain pollutants and unhealthy lifestyles can alter sperm. In addition to animal studies, a 2013 study showed that epigenetic signatures of endocrine disruptors can be transferred between generations, suggesting that transgenerational effects can occur.
DNA methylation
This research shows the importance of DNA methylation in the epigenetic transgenerational actions of a class of compounds known as endocrine disruptors on male sperm. The results of their study show that endocrine disruptors impair the function of the male Sertoli cells. This effect is attributed to altered binding sites of the SRY gene, which controls sex.
The authors of this study compared the levels of DNMT1 and DNMT3a in embryonic testes from different generations, including the F0, F1 and F2, but there was no difference between the F3 generation. This study shows that DNA methylation is a fundamental process during development. DNA methylation affects the function of multiple biological processes, including X-chromosome inactivation.
These EDCs interfere with DNA methylation during epigenetic reprogramming, a process that affects all tissues of the organism. DNA methylation affects all three embryonic germ layers and all subsequent generations. The effects of erasure are common in both sexes, while the effects of remethylation are sex-specific.
Histone modifications
Epigenetic modification of DNA regulates gene expression, and abnormalities in this process could lead to male infertility. Aberrant epigenetic modification of sperm DNA may also lead to defects in male fecundity. The role of aberrant epigenetic modifications in male infertility remains unclear, but it may be involved in a number of diseases.
While the role of histone modifications in the transgenerational actions of endocrine-disrupting environmental chemicals is well-established, the exact mechanisms are still unclear. To understand these processes, researchers have emphasized that epigenetic modifications in other cells, besides DNA methylation, are also involved. This information is incredibly valuable, as it provides a much better understanding of how these molecules alter gene expression.
In addition to these mechanisms, epigenetic alterations of sperm DNA may also negatively affect male fertility and the development of embryos. These alterations occur during mitosis and may cause specific genes to be repressed or untranscribed, or induce chromosomal non-disjunction. They may also result in the occurrence of double-strand breaks or other chromosomal abnormalities. Lastly, altered epigenetic patterns can increase the risk of adult pathologies in offspring.
Chromatin structure
Environmental exposures to EDCs alter sperm epigenomes. This information is passed to offspring of subsequent generations. The effects of environmental exposures on sperm epigenomes in male mice can be transgenerational. Epigenetic changes in sperm are responsible for a variety of phenotypes in subsequent generations.
Exposure to endocrine disruptors has been linked to adult-onset disease, decreased sperm quality, and reduced spermatogenic capacity. The effects of transient exposure to endocrine disruptors are also associated with adult onset disease. Transgenerational inheritance of the effects of endocrine disruptors in the germline are linked to altered DNA methylation patterns.
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In humans, a combination of maternal and paternal alleles is required to pass on the disease from one parent to the next. In mice, endocrine disruptors alter spermatogenesis, with one copy of a gene escaping demethylation after fertilization. It is not clear whether these disruptions also affect the male oocyte.
Moreover, histone modification has been associated with different states of chromatin organization. Among the histone variants H2A.Z is associated with active gene expression, whereas H3.3 is associated with transcriptionally inert chromatin. Furthermore, different modifications affect transcriptional activity and recruit transcriptional cofactors to the chromatin. Some of these modifications can also modify the ubiquitin-ligase activity of HAT, including histone acetylation at lysine four and monobutyltin.
DNMTs in embryonic testes
These findings indicate that endocrine disruptors affect the expression of genes regulated by DNMTs. Although alterations in the activity of DNMTs do not directly affect the phenotypes of the F3 generation, the transgenerational actions of endocrine disruptors on male ferti may be affected by alterations in the epigenome.
Microarray analysis of testis from F1-F3 generation animals showed that DNMTs were significantly increased. However, there were no significant differences between control-treated and vinclozolin-treated testes. RNA was pooled from three litters for each experiment, and RNA from two independent vinclozolin-treated F1-F3 generations was used to determine the effects of vinclozolin on DNMT expression.
The results of the current study suggest that DNMTs regulate the expression of genes and the transcriptome of developing organs. Endocrine disruptors vinclozolin and a hormone called clomiphene have the potential to cause transgenerational adult-onset diseases in sperm and in male ferti.
Regulation of ER expression
The current study demonstrates that environmental toxins promote the epigenetic transgenerational inheritance of disease. The transgenerational disease phenotypes in male sperm were associated with exposure specific epigenetic DNA methylation or epimutations. These changes were correlated with unique subsets of genes and altered transcriptomes.
These results suggest that endocrine disruptors affect fetal reproductive tissues during pregnancy and in lactation. Some endocrine disruptors, such as the herb vinclozolin, induce the expression of the CaBP-9k gene in male rats, a process known to contribute to increased male infertility. Endocrine disruptors can also induce a transgenerational disease phenotype in male sperm.
In the study, BPA, an environmental chemical with estrogenic activity, regulates the expression of genes involved in E2-response transcription in ER-positive BG-1 cells, which would serve as the most sensitive in vitro model for the detection of estrogenic EDCs. Xenoestrogens, at nanomolar concentrations, induce membrane estrogen receptor-alpha-mediated Ca2+ fluxes and prolactin release in GH3/B6 pituary tumor cells.
The genetic and environmental deterministic aspects of disease are interwoven and complex. However, the classical genetic determinism concept suggests that genes with only a few mutations are the primary determinants of disease etiology. In this regard, the study demonstrates that epigenetics plays a major role in determining disease susceptibility.
Effects on spermatogenic capacity
Some of the effects of endocrine disruptors on male spermatogenesis have been identified through genetic studies. One of the most common genetic disorders is azoospermia, and this disease can also occur due to chromosomal aberrations. For example, Y chromosome deletion may cause oligozoospermia. Another genetic condition is single nucleotide polymorphism (SNP), which is correlated with male infertility.
Endocrine disruptors, such as pesticides, phthalates, and herbicides, are known to affect male reproductive functions. They have been associated with decreased spermatogenic capacity, including low semen volume and a low total sperm count per ejaculation. These findings suggest that the effects of endocrine disruptors on male sperm might depend on individual genetic variations.
Testicular hormones are crucial for the development and maturation of spermatogenesis. The effect of these hormones on the testis is vital for most aspects of male masculinization. Testosterone is the most important hormone, essential for the meiotic process and subsequent differentiation of spermatoids. Testosterone exerts its action by stimulating protein synthesis during specific periods of spermatogenesis.
