Open access peer-reviewed chapter
Abstract
Male fertility has declined over the last few decades. Therefore, the increasing concern about the link between the environment and male reproductive health has been raised. Studies have found that the exposure to environmental toxicants during fetal development or the mother’s perinatal period promotes the occurrence of infertility in adult male offspring. Environmental toxicants, especially endocrine disrupting chemicals (EDCs), such as phthalic acid ester (PAEs), can induce changes in epigenetic information related to paternal infertility, threatening the reproductive, and developmental health of offspring. Transgenerational epigenetic inheritance refers to a genetic phenomenon that does not involve DNA sequences and affects the phenotypic characteristics of offspring by altering gene expression through DNA or RNA methylation, histone modification, noncoding RNAs, etc. This review describes the concept and phenotype of intergenerational and transgenerational inheritance induced by EDCs, summarizes the recent achievements of important epigenetic molecular mechanisms, and provides a relevant theoretical basis for the protection of male fertility.
Keywords
- transgenerational inheritance
- endocrine disrupting chemicals
- male infertility
- DNA methylation
- m6A modification
1. Introduction
At least 180 million couples worldwide are affected by infertility, with male factors accounting for approximately 50% [1]. Levine et al. found through a meta-analysis that during the decades from 1973 to 2011, there was a significant decrease in sperm count among males from North America, Europe, and Australia, with no trend toward remission [2]. They further explored and found that such a phenomenon also existed in males from South America, Asia, and Africa. The declining trend continues and has become even steeper since 2000 [3]. The findings above strongly indicate that there has been a significant decline in male reproductive health in the past 50 years, leading to significant fertility issues that cannot be ignored.
Many factors can cause male infertility, mainly known as Klinefelter syndrome, varicocele, environmental or occupational exposure to toxic chemicals [4], heavy metals [5, 6], smoking [7] and drinking [8], etc. Experimental and epidemiological studies show a strong connection between exposure to environmental endocrine-disrupting chemicals (EDCs) and impaired male fertility [9, 10, 11]. EDCs refer to “an exogenous chemical substance released into the environment due to human production or life, interfering with hormone action in humans and animals,” which damage the homeostasis of the endocrine system by inhibiting or promoting hormone production, secretion [12] and transport [13, 14] in the body, which raise a worldwide public health concern [15, 16].
Exposure to EDCs during pregnancy will lead to damage to testicular function, spermatogenesis disorder, and fertility decline of offspring [17]. EDCs, such as bisphenol A (BPA), enhance susceptibility to diseases, especially male reproductive system diseases [18], which are significantly correlated with epigenetic variations [19]. Epigenetics refer to the mechanism by which genetic information of related traits is transmitted to offspring through DNA or RNA methylation, histone modification, noncoding RNA, and so on, without changing DNA sequences [20]. Obvious abnormality of DNA and histone methylation (e.g., H3K4me and H3K27me) can be observed in the sperm of men with reproductive disorders [21].
Changes in epigenetic information caused by ancestral exposure can still be transmitted to offspring without direct exposure to environmental factors, which is known as epigenetic transgenerational inheritance [22, 23]. Yuan et al. found that there was a decline in the number of sperm and Sertoli cells in the generations, from F1 to F3, of male Sprague–Dawley rats whose ancestral female rats (F0) were exposed to BPA during pregnancy [24].
When it comes to transgenerational inheritance, it is necessary to define phenotype to make a distinction between direct exposure effects and germ-cell-mediated transgenerational effects [25]. Take EDCs exposure for example. If the pregnant female (F0) is exposed to EDCs, the developing embryo (F1) and the germ cells (F2) that have occurred in the embryo are also directly exposed to EDCs. Therefore, the first generation which is not directly exposed to EDCs is the F3 generation. If the nonpregnant female (F0) is exposed to EDCs, the germ cells that produce the F1 generation are also directly exposed to EDCs, while the F2 generation is not directly exposed to EDCs [21, 23]. In both cases above, postnatal exposure assessment should be conducted for F3 or F2 to identify transgenerational inheritance.
2. Epigenetic mechanism
2.1 DNA methylation
DNA methylation is one of the important epigenetic modifications in cells. Due to the semi-reserved nature of DNA replication, the DNA methylation pattern on the parent chain can be replicated on the newly synthesized subchain, realizing the inheritance of DNA methylation [26]. It was found that abnormal sperm DNA methylation was negatively correlated with semen quality, spermatogenesis, and male fertility [27]. In eukaryotes, DNA methyltransferases (Dnmts), which promote and maintain DNA methylation [28], and coregulate gene expression with demethylase TET dioxygenase [29], catalyze the methylation of cytosine at C5 to form 5-methylcytosine (5mC), the main form of DNA methylation [30]. 5mC is a stable epigenetic marker of transcriptional inhibition in gene enhancers and promoters.
The key feature of DNA methylation is the symmetrical 5mC modification of CpG dinucleotide [31], usually found in the promotor of DNA, where methylation causes gene silencing [27]. The region with high sequences of CpG is called CpG island (CGI). Imprinted genes can still retain the methylation pattern of parental allele after global genome demethylation after fertilization [27]. Song et al. found that poor semen parameters, which can prompt semen quality, were highly related to abnormal methylation at some CpG sites of imprinted genes, including spermatogenesis disorder and severe damage to DNA integrity [32].
A recent research conducted by Takahashi et al., based on the completion of CGI-targeted methylation on metabolic-related genes (Ankrd26 and Ldlr) of embryonic stem cells (ESCs) in mice, found that DNA methylation-edited mice showed abnormal metabolic phenotype, and this acquired methylation could be passed on in offspring [33]. The author inserted a DNA fragment that is free of the CpG site into the CGI near promotor to induce de novo DNA methylation of the CGI. When the DNA fragment was removed, the state and level of the methylation remained unchanged in the offspring mice, resistant to demethylation after fertilization [34, 35].
Thorson et al. explored the transgenerational effects of pesticides on the male reproductive ability by constructing a pesticide (permethrin and DEET combination) infected mouse model. They found that if the pregnant female (F0) was exposed to pesticides, abnormal spermatogenetic phenomena such as atrophy of seminiferous tubule and spermatogenic arrest, were observed in the testis of both F1 and F3 generation, as well as specific differentially methylated regions (DMRs) in sperm [36]. Consistently, exposure of the F0 female mice to p,p’-DDE during pregnancy led to changes in DNA methylation levels of H19 and Gtl2 in the sperm of the F1 male mice, which was transferred to the F3 generation through the paternal germ line [37].
The findings above highly demonstrate that the DNA methylation pattern can be transferred across generations through the parental germ line.
2.2 RNA methylation
N6-methyladenosine (m6A) is generated after methylation at the 6th nitrogen atom of adenine, which is the most common endogenous posttranscriptional modification (PTM) of mRNA in eukaryotes [38], affecting cycle stages of mRNA from processing, output, translation to degradation [38, 39]. The m6A modification occurs on various RNAs, including protein-coding transcripts, like mRNAs, tRNAs, and rRNAs, and noncoding RNAs, like lncRNAs [40].
The biological function of m6A modification is mediated by methyltransferase, demethylase, and binding proteins, dynamically and reversibly [41, 42]. The imbalance of m6A modification is related to spermatogenesis disorder and infertility in males [43]. A recent study found that FTO, a demethylase, regulated testosterone receptor AR dependent on m6A, affecting the maturation of Leydig cells and spermatogenesis [44].
Chen Y et al. observed that m6A methylation affected the transcriptional stability of CAMKK2β, a calcium-dependent protein kinase that suppressed AMP-activated protein kinase (AMPK) and the translation of PPM1A, a magnesium-dependent protein phosphatase that promoted AMPK expression to modulate autophagy, thereby regulating testosterone synthesis in Leydig cells. As well, a significant decline of m6A methylation was observed in Leydig cells from patients with oligospermia or azoospermia [45]. The research indicated that m6A methylation had important implications for male reproductive health.
Research has shown that injecting sperm tsRNAs from high-fat diet mice into normal zygote would cause metabolic disorder in offspring, suggesting that paternal phenotypes can be transmitted across generations through sperm tsRNAs [46]. But, this effect disappeared in Dnmt2−/− mice. Simultaneously, RNA methylation levels significantly decreased, leading to changes in the structure and function of tsRNAs, which pointed out the importance of RNA methylation in the occurrence of transgenerational inheritance [47]. However, the role of m6A modification in the epigenetic transgenerational inheritance of male infertility has not been elucidated, and further research is needed.
2.3 Histone modification
Chromatin carries genetic information and consists of nucleosome and histones, which includes H2A, H2B, H3, and H4 [48]. Environmental factors can affect the density of chromatin or signal transduction of transcription factors by inducing posttranslational modifications (PTMs) of histones [49], which are often referred to as epigenetic marks, including methylation, phosphorylation, acetylation, ubiquitination, etc., to regulate chromatin structure and gene expression [50, 51].
In most species, lysine methylation is the frequent form of histone modification. Chromatin inhibition is related to the enrichment of H3 lysine 9 trimethylation (H3K9me3) [52] and H3 lysine 27 trimethylation (H3K27me3) [53], while H3 lysine 4 trimethylation (H3K4me3) [54] peaking around the transcriptional start site (TSS) produces a marked effect in the process of the initiation of transcription [55]. It was found that the inhibition of H3K4 methylation during spermatogenesis, possibly related to the decrease of transcriptional activity of developing sperm, led to developmental defects and health damage of offspring, which was transmitted paternally for three generations, indicating that epigenetic modification of sperm has an impact on the health of offspring [56, 57].
Histone modification is jointly regulated by lysine methyltransferase (KMT) enzymes and demethylase (KDM) enzymes, identifying methylation sites through binding proteins to participate in various biological processes [58]. Ribeiro et al. found that GCNA, a histone-binding protein whose mutations in locus were responsible for azoospermia in men [59], played a crucial role in long-term spermatogenesis [60]. It was reported that H3K4me3 was involved in the formation of double-strand breaks (DSBs) during the meiosis of spermatogonium, which is related to spermatogenesis. In this process, Cfp1, a component of KDM enzymes, is dynamically expressed to protect meiosis [61].
An animal experiment carried out by Skinner et al. showed that being exposed to DDT, a kind of EDCs, during the pregnancy of female mice (F0) was responsible for the alteration of H3K27me3 methylation level in the sperm of the F3 male mice, generating apoptosis of testicular germ cells, which was linked to differential histone retention regions (DHRs). However, it was not observed in the F1 or F2 generation [62]. This suggested the critical role of histone modification in the transgenerational inheritance induced by EDCs.
2.4 Noncoding RNAs
Noncoding RNAs (ncRNAs) refer to RNAs that do not participate in encoding proteins, including small noncoding RNAs (sncRNAs), which cover microRNAs (miRNAs), small interfering RNAs (siRNAs), etc., long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), etc. [63]. NcRNAs are involved in mediating cellular biological processes, including gene expression, PTMs, and signal transduction, regulating individual development and disease [64, 65].
In eukaryotic cells, ncRNAs modulate various physiological processes, including spermatogenesis and spermatozoa maturation, by up or down-regulating gene expression [66]. Research showed that reduced expression of miR-525-3p was related to poor sperm quantity, quality, and morphology in patients with asthenozoospermia [67].
Recently, the effect of sperm sncRNAs in regulating early life development and epigenetic inheritance has been focused on. It makes transgenerational inheritance possible that sncRNAs mediate other epigenetic mechanisms, like DNA methylation and histone modifications [68]. Liu et al. found that sperm sncRNAs, including tsRNAs and rsRNAs, provided support for the transgenerational inheritance of paternal metabolic disorder phenotype [69].
It was reported that prenatal dexamethasone exposure resulted in changes in testicular morphology, with the decrease of Leydig cells and the inhibition of testosterone production in offspring male mice, consistent with the effect of the F3 generation. Liu et al. discovered that the expression of miR-466b-3p declined in sperm of both F1 and F3 male mice, which indicated that miR-466b-3p may mediate the transgenerational effects of reproductive toxicity induced by dexamethasone [70].
CircRNAs are found in human testis, sperm, and seminal plasma while studied limitedly, making it a novel object in the field of male reproduction. It was reported that circRNAs may be associated with sperm quality control [71], DNA replication, cell cycle, and meiosis [72]. A significant difference was observed between the expression level of circRNAs in the sperm of asthenozoospermic patients and normozoospermic males [73].
3. Transgenerational inheritance induced by EDCs
3.1 Phthalic acid esters (PAEs)
Plastics are widely used in daily life, exposed through Inhalation, ingestion, and dermal absorption [74]. PAEs, such as di (2-ethylhexyl) phthalate (DEHP) and dibutyl phthalate (DBP), are frequently-used plasticizers in plastic products, which have teratogenicity, carcinogenicity, mutagenicity, and reproductive toxicity, posing a serious threat to human reproductive and developmental health [75].
An epidemiological study found that PAE exposure was associated with a decrease in male reproductive quality [76, 77]. Yang et al. discovered that in adolescent SD rats, DEHP inhibited the expression of Sod2, Igf-1, and Gpx1 by upregulating the methylation level of the CpG sites around promotor regions, resulting in injury of testis, including decreased serum testosterone level, apoptosis of spermatogenic cells, dysfunction of Leydig cells, etc. [78]. Another research came to the consistent conclusion that DEHP exposure reduced the expression of antioxidant indicators in testes, such as Cat, Sod1, Prdx6, and Sirt1, thus increasing the production of reactive oxygen species (ROS), which significantly affected the proliferation of germ cells, leading to poor sperm quality and male infertility [79].
The phenotype of male reproductive disorders caused by PAEs exposure can be passed on to offspring through the paternal germ line. Doyle et al. found that the morphology of the testicular seminiferous tubule of male offspring, from the F1 generation to the F4 generation, whose female ancestry was exposed to DEHP during pregnancy was abnormal; meanwhile, the sperm count and motility of male offspring were reduced. Damage to the function of spermatogonial stem cells (SSCs) was also found in the F3 generation [80].
The exact molecular mechanism of the transgenerational inheritance of the function disruption in germ cells and SSCs remains unclear, but there have been articles indicating that disease-specific DMR is found in the sperm of the F3 male rats [81]. It was reported that gestational exposure to DEHP led to impaired male reproductive function and increased DNA fragmentation index (DFI) across generations. Hsu et al. discovered in the F3 generation that compared to the control group, DMRs were observed in all DEHP exposure groups, with more in the group which was highly exposed [82].
3.2 Bisphenol a (BPA)
BPA is an industrial plasticizer that is widely consumed [83] with estrogenic activity, which can bind to androgen receptors and act as an antagonist to block the function of endogenous androgen [84]. The study found that increased BPA concentration in male urine was significantly related to spermatogenesis disorder and poor semen quality [85]. BPA has a transgenerational impact on the reproductive ability of offspring [86] by affecting sperm epigenetic modulations, including improving global DNA-specific CpG site methylation and decreasing histone modifications [87].
Ryu et al. found that BPA caused the elevation of H3 modification and DNA methylation in the testis, affecting the expression level of core histones, which interfered with the transformation from histone to protamine during spermatogenesis, thus leading to spermatogenesis disorder and fertility decline [88]. An experiment conducted on zebrafish also confirmed the conclusion that BPA caused male infertility. González-Rojo et al. found that BPA led to a rise in the activity of histone acetyltransferase, increasing the acetylation level of histones (H3K9ac, H3K14ac and H4K12ac). What is more, the acetylation effect can be transmitted across generations paternally [89].
Animal toxicity experiments are often limited to exposure to individual toxic substances. An epidemiological study investigated the relationship between bisphenol A and its analogs in urine and semen quality [90]. It was found that high BPA exposure was negatively correlated with semen concentration, sperm count, and motility, while high BPS exposure was negatively correlated with sperm motility. When bisphenol mixtures were more than 55th percentiles, the impairment of semen quality was also observed.
3.3 Per- and polyfluoroalkyl substances (PFAS)
Per- and poly-fluoroalkyl substances (PFAS) are a kind of organic compound mainly composed of carbon and fluorine atoms, which are widely used in textiles, surfactants, food packaging, and other fields. However, because of their high thermal stability and chemical stability, they can persist in the environment and not be biodegraded [91]. PFAS exposure is associated with multiple adverse outcomes, including reproductive and developmental toxicity [92].
It was found that high exposure to perfluorinated compounds (PFCs) led to male gonadal dysplasia, decreased sperm count and semen quality, and increased infertility, as well as lower levels of testosterone and proliferation of Leydig cells [93, 94, 95]. The reproductive toxicity caused by PFAS exposure is related to changes in membrane permeability, disruption of mitochondrial function, disruption of blood-testis barrier (BTB), decreased gonadotropin-releasing hormone (GnRH) secretion, and so on [96].
There has been no literature report on the transgenerational inheritance of PFAS reproductive toxicity. This is a gap and challenge in the field of male reproduction. Strict research is still needed in the future.
4. Discussion
This review summarizes the epigenetic mechanisms and transgenerational inheritance of male infertility caused by environmental endocrine-disrupting chemicals. In the field of male reproduction, DNA methylation, histone modification, and noncoding RNAs have been studied relatively thoroughly, although people seem to be more interested in the molecular biological mechanism which mediates toxicological reactions occurred in offspring.
Like methylation, acetylation, and ubiquitination, SUMOylation as a kind of posttranscriptional modification has gradually attracted attention and research, which is reported that mediates the localization and function of target proteins by binding to them [97]. SUMOylation regulates chromatin structure and gene expression by PTMs on histones [98]. Nowadays, few researchers have associated SUMOylation with male reproduction, let alone the transgenerational inheritance of phenotypes of reproductive disorders. This may be an innovation of research in the field of reproduction in the future.
NcRNAs make it possible for transgenerational gene regulation [68]. There is clear evidence in cancers that lncRNAs can mediate DNA methylation in both physiological and pathological conditions, as well as histone modifications and chromatin remodeling, regulating various transcription processes [99]. Similarly, it is found that PIWI-interacting RNAs (piRNAs) mediate de novo DNA methylation in paternal germ cells [100]. However, few researchers have combined ncRNAs with other epigenetic mechanisms to explain the occurrence of related phenotypes in male infertility.
Although significant progress has been made in the research on the basic mechanism of transgenerational inheritance, the relationship between epigenetics and environmental exposure is still unclear, and most of them are carried out in animals. Therefore, it is not clear whether there is a similar mechanism in humans. Combining population data with animal experiments can promote research on the transgenerational inheritance of male reproductive disorders induced by EDCs.
The results of existing research findings show that many reproductive diseases and infertility today may be partially mediated by environmental exposure to ancestry across generations [101]. Genetic factors and heritability should be taken into consideration in the risk assessment of reproductive diseases, and relevant epigenetic markers should be used to assist in diagnosis to prevent or reduce the occurrence of diseases.
5. Conclusions
This review summarizes the recent achievements of important epigenetic molecular mechanisms, such as DNA or RNA methylation, histone modification, ncRNAs, and transgenerational inheritance induced by environmental endocrine-disrupting chemicals, such as PAEs, BPA, and PFAS. In this review, the transgenerational epigenetic phenotype is clearly defined. At the same time, it is proposed to combine ncRNAs with other epigenetic mechanisms to explain the mechanism of transgenerational inheritance of male infertility.
Acknowledgments
This work was supported by the National Key Project of Research and Development Program (2022YFC2702902), National Natural Science Foundation of China (82273662, 81971405), Jiangsu Natural Science Foundation (BK20221307), Major Project of Natural Science Research in Jiangsu Province Colleges and Universities (20KJA330001), Medical Research Project of Jiangsu Health and Health Commission (Z2019010), the Major Research plan of the National Natural Science Foundation of China (91943301), and the Priority Academic Program for the Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine).
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