|Year : 2017 | Volume
| Issue : 2 | Page : 89-99
Environmentally induced paternal epigenetic inheritance and its effects on offspring health
Zheng-Hui Zhao1, Heide Schatten2, Qing-Yuan Sun1
1 State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Beijing 100101, China
2 Department of Veterinary Pathobiology, University of Missouri, Columbia, MO 65211, USA
|Date of Web Publication||17-Oct-2017|
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101
Source of Support: None, Conflict of Interest: None
Increasing evidences indicate that chronic diseases in offspring may be the result of ancestral environmental exposures. Exposures to environmental compounds in windows of epigenetic susceptibility have been shown to promote epigenetic alterations that can be inherited between generations. DNA methylation, histone modifications, and noncoding RNAs are sound mechanistic candidates for the delivery of environmental information from gametes to zygotes. This review focuses mainly on paternal exposures and assesses the risk of epigenetic alterations in the development of diseases, providing insights into relationships between aberrant sperm epigenetic patterns and offspring health. Elucidation of the mechanisms underlying environmental epigenetic information that survive from epigenetic reprogramming and its transmission to future generations may hold a great promise for providing therapeutic targets for epigenetic diseases associated with environmental exposures.
Keywords: Environmental Exposures; Offspring Health; Sperm; Transgenerational Epigenetic Inheritance
|How to cite this article:|
Zhao ZH, Schatten H, Sun QY. Environmentally induced paternal epigenetic inheritance and its effects on offspring health. Reprod Dev Med 2017;1:89-99
|How to cite this URL:|
Zhao ZH, Schatten H, Sun QY. Environmentally induced paternal epigenetic inheritance and its effects on offspring health. Reprod Dev Med [serial online] 2017 [cited 2020 Aug 6];1:89-99. Available from: http://www.repdevmed.org/text.asp?2017/1/2/89/216862
| Introduction|| |
For the past decades, the prevalence of chronic diseases such as obesity, diabetes, cancer, and cardiovascular disease indicates an increasing emergency to determine causes and origins worldwide., Unlike monogenic diseases, the pathogenesis of chronic diseases is complex and multifactorial in origin. More and more evidences suggest that environmental exposures such as endocrine-disrupting compounds, stress, and dietary factors may be responsible for the increased incidence of chronic diseases, which also has a severe impact on an offspring's health.,,, However, the majority of environmental determinants do not have the capacity to change the DNA sequence but can promote epigenetic alterations. Accordingly, the analysis of environmentally induced epigenetic inheritance between generations appears to be the most adequate approach to explain such conditions.
The sperm is a kind of highly specialized cell that can transmit epigenetic information to the zygote.,, It is becoming clear that alteration of the sperm epigenome is closely linked to environmental exposures. Hence, environmental epigenetic inheritance involves the transmission of aberrant sperm epigenetic profiles between generations, which promotes disease development even though offspring is not directly affected by environmental factors., However, the largest barrier to environmental epigenetic inheritance is epigenetic reprogramming between generations, and during this process, DNA methylation, histone modifications, and noncoding RNAs all become reset., Nevertheless, accumulating evidences indicate that certain epigenetic modifications can survive reprogramming and they are transmitted from sperm to embryos, suggesting that sperm epigenetic marks can be inherited and play a pivotal role in early embryonic development and the offspring's health.,,,,, Furthermore, increasing literatures on epigenetic reprogramming show that certain environmentally induced epigenetic marks may be metastable and not completely erased across generations, which also supports the inheritance of epigenetic modifications.,,,
In light of the increasing data for the transmission of epigenetic information across generations, it is becoming clear that paternal environmental exposures play a key role in shaping the offspring's epigenetic patterns and health status [Figure 1], which may further promote the development of various chronic diseases.,, However, the underlying mechanisms that lead from environmental exposures to epigenetic alterations remain elusive. In addition, plausible biological mechanisms for the transmission of environmental effects between generations have not yet been reported in the literature. Here, we discuss the current status of progress regarding the effects of paternal environmental exposures on the offspring's health and investigate the etiology of chronic diseases in the offspring that are dramatically influenced by environmental factors. Moreover, we also explore the molecular mechanisms involved in the survival of environmental epigenetic information following epigenetic reprogramming across generations. Finally, epigenetic marks that play a pivotal role in the diagnosis and therapy for an offspring's chronic diseases are also being considered.
|Figure 1: Various degrees of environmental epigenetic effects on human health. Epigenetic modifications are sensitive to environmental factors. During spermatogenesis, environmental exposures at sensitive windows may likely alter the epigenetic patterns of sperm, which further causes impaired fertilization, spontaneous abortions or epigenetic associated diseases in offspring.|
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| The Contributions of the Sperm Epigenome to Early Embryos|| |
Spermatogenesis is a complex developmental process that is regulated by dynamic epigenetic modifications to generate highly specialized mature sperm with specific epigenetic profiles. The epigenetic profiles presented mainly as DNA methylation, histone modifications, and noncoding RNAs are transmitted to the oocyte through fertilization and play an important role in the development of early embryos.,, It is, therefore, not surprising that aberrant sperm epigenetic patterns have a severe impact on early embryonic development and that it is closely associated with several chronic diseases in descendants.,,
| DNA Methylation|| |
DNA methylation catalyzed by DNA methyltransferases (DNMTs) to add a methyl group to the 5th carbon of cytosine in cytosine–phosphate–guanine (CpG) dinucleotides is thought to be a heritable epigenetic modification implicated in many well-identified epigenetic inheritance examples. In general, high and most intermediate densities of CpG promoters are hypomethylated in the sperm, while low-density CpG promoters are predominantly hypermethylated, which is significantly different from that of somatic cells but it is similar to embryonic stem (ES) cells. Several studies have shown that hypomethylated CpG promoters in sperm are bound to the self-renewal and developmental transcription factors in human ES cells. In contrast, Smallwood et al. observed that several methylated CpG islands could escape reprogramming and exhibit incomplete demethylation during embryogenesis. However, the DNA methylation patterns in sperm contributing to early embryos are largely enriched at intergenic regions, which presents a markedly negative correlation between gene expression and promoter methylation status. Furthermore, non-CpG methylation also exists in male germ cells and embryos, which is enriched mainly in transcriptionally active regions to promote gene activation.,, In addition, a number of reports have suggested that DNA methylation patterns can largely be maintained at the differentially methylated regions of the imprinted genes. Moreover, certain classes of retrotransposons and nonimprinted genes have also been shown to be unchanged from sperm to early embryos., These studies indicate that DNA methylation patterns in sperm can be potentially transmitted to the offspring as environmentally influenced epigenetic information carriers.
However, there are two waves of epigenomic reprogramming that involve the erasure and reestablishment of DNA methylation. One epigenetic reprogramming process occurs at the onset of male germ cell development and the other begins at the early stage of embryogenesis. From the primordial germ cells (PGCs) to mature sperm, the programming of DNA methylation involves waves of DNA demethylation and remethylation, and proper regulation of these events is essential for normal function of the mature sperm and proper imprinting of the male gametes. Thus, the sperm can transmit the specific methylation patterns through the fertilization process. After fertilization, extensive erasure of DNA methylation occurs to establish the full potential for the development of early embryos. Previous studies have shown that a rapidly active demethylation of the paternal genome occurs through dioxygenase ten–eleven–translocation 3 (TET3) that is enriched specifically in the male pronucleus, resulting in the modification of 5-mC to 5-hmC. In the paternal genome, both the active and passive demethylation loci are largely intergenic, which could arise from a higher overall level of intergenic methylation previously noted in sperm. In general, the paternal genome in early embryos appears to undergo a global demethylation to create a hypomethylated epigenome of the inner cell mass before the blastocyst stage. It is, therefore, obvious that survival mechanisms must exist to facilitate the escape of certain DNA methylation marks during genome-wide reprogramming.
| Histone Retention and Modifications|| |
The N terminal and C terminal tails of histones are subjected to posttranslational modifications. These processes consist of methylation, acetylation, phosphorylation, ubiquitylation, etc., with 16 types of histone modifications identified to date. The timing for the establishment and removal of histone modifications is essential for male germ cell and early embryonic development. Each of these modifications works alone or in concert with others, under the name of “histone code” to regulate gene expression through mediating the contacts between nucleosomes and the recruitment of nonhistone proteins. In this section, we focus mainly on the histone methylation and acetylation that are transmitted from sperm to the oocyte and have an impact on embryogenesis.
During spermatogenesis, the methylation level of H3K4 peaks in spermatogonia, which is essential for stem cells to begin differentiation and continue to become spermatocytes. Meanwhile, the histone H3 lysine demethylase KDM1A existing in spermatogonia is closely linked to the low level of H3K9 and H3K27 at this stage, which may also be necessary for the differentiation of spermatogonia. Subsequently, the methylation levels of H3K9 and H3K27 increase in spermatocytes, in which H3K9 methylation in the promoters is implicated in the silencing of euchromatic genes as well as the formation of heterochromatin, and the removal of H3K9me at the late stage of meiosis is essential for the onset of spermiogenesis. In addition, the trimethylation of noncanonical histone H3.3 variant was shown to be abundant at the retained regions that are enriched in CpG sequences but lack DNA methylation., Moreover, other noncanonical histone variants have also been reported to be present in the retained nucleosomes of mature sperm. TH2B, for instance, was recently shown to be enriched in genes involved in spermiogenesis, directing histone to protamine transition via replacing canonical H2B. Furthermore, recent studies have demonstrated that histone retentions also occur at specific developmental gene loci in mature sperm, and these retentions primarily associated with H3K4me2, H3K4me3, and H3K27me3 raise the possibility that these histone modifications can be inherited across generations as carriers of epigenetic information. H3K4me2 becomes enriched at promoters of developmental genes and is involved in spermatogenesis and cellular homeostasis. H3K4me3 appears at a subset of promoters of the highly expressed developmental genes, paternally expressed imprinted loci, and certain noncoding RNA promoters. H3K27me3 is generally linked to developmental and signaling transcription factors. Moreover, the vast majority of the promoters associated with embryonic development usually contain both an activation mark (H3K3me3) and a silencing mark (H3K27me3), thus providing another regulatory mechanism through which the paternal DNA is poised for activation at specific sites required for normal embryogenesis, reinforcing its role in the regulation of embryogenesis.
Following fertilization, the compacted sperm chromatin must be reorganized from its highly compacted and transcriptionally quiescent state to an inducible one, facilitating the needs of early embryos. The nucleosomes retained in sperm chromatin exhibit specific sites for the developmentally important loci and for the histone differential modifications at these positions. Ziegler–Birling et al. found that the acetylation of H3K64, H3K56, and H3K122 occurs throughout preimplantation embryos. The acetylation of histones in paternal chromatin has a negative effect on the generation of higher order structures, which is essential for protamine to histone exchange. The acetylation on lysines 9, 14, and 18 of H3 and lysines 5, 12, and 16 of H4, which are derived from the maternal genome, are incorporated into the paternal chromatin. Immediately after the exchange of protamines to histones, the DNA demethylation of the paternal genome occurs. When ES cells begin differentiation, the bivalent domains tend to preserve either the activating H3K4me or the repressive H3K27me modification, but not both. These results indicate that transcription factors that control certain differentiation processes are kept in a poised, low-level expression state within the ES cells by having a bivalent cluster of modifications. This also shows that the preservation of pluripotency of the ES cells and the differentiation of the ES cells can be manipulated by the selective regulation of modification pathways. In ES cells, H3K27me3 is located in discrete, punctate regions coinciding almost exclusively with CpG islands, which are generally devoid of DNA methylation. From fertilization to the two-cell stage, the levels of H3K27me and maternal DNA methylation are high, but the paternal DNA methylation level is decreasing. Accordingly, we could speculate that H3K27me3 is located preferentially on the paternal genome and exclusive of DNA methylation. Interestingly, promoters that are marked with H3K27me3 in ES cells are more likely to gain DNA methylation during differentiation than those lacking H3K27me3. The detailed mechanism between H3K27me3 and DNA methylation requires further research.
| Noncoding RNAs|| |
Besides DNA methylation and histone modifications, the ncRNAs in sperm represent another carrier that is essential for delivering epigenetic information, potentially resulting in phenotypic changes in the offspring. The types of ncRNAs mainly including miRNAs, siRNAs, and piRNAs are involved in the transmission of environmentally induced epigenetic information., The paternal ncRNAs that are unique to the sperm can be detected in the developing zygote, which supports the hypothesis that sperm-derived RNAs can transmit environmental information to the next generations.,
Spermatogenesis is a well-coordinated process that requires a timely and tightly coordinated regulation of numerous genes. The miRNA and piRNA pathways are involved in the stage-specific control of gene expression during the whole process of spermatogenesis. miR-34c is the most abundant sperm miRNA, which has been identified in spermatogonial stem cells (SSCs) to maintain the population of the SSC. Moreover, miR-34c is also highly expressed in spermatocytes and round spermatids to prevent the germ cell from testosterone deprivation-induced apoptosis. Furthermore, Liu et al. showed that sperm-derived miR-34c is required for early embryonic cell division through negatively regulating the expression of B-cell leukemia/lymphoma 2. Likewise, pri-miRNA-181c, the most abundant immature miRNA in human sperm, is a critical element for early embryonic development. In addition, during the process of maturation in the epididymis, sperm can uptake novel miRNAs that also have a potential impact on embryonic development and may promote environmentally induced epigenetic inheritance across generations., On the other hand, according to the specific stage of an expression, piRNAs are mainly classified into the prepachytene and pachytene piRNAs. The prepachytene piRNAs are enriched in repeat-derived sequences, while the pachytene piRNAs are enriched in the intergenic, unannotated sequences. In the paternal germline, piRNAs have been shown to play pivotal roles in the establishment of paternal imprints via de novo DNA methylation at the imprinted loci. In addition, transposable elements (TEs) are mobile genetic elements that confer on them a high mutagenic potential when they are expressed unconstrainedly during spermatogenesis. In prospermatogonia, prepachytene piRNAs are essential for the silencing of TEs to guarantee genome stability via establishing de novo DNA methylation at the mobile sites. In spermatocytes and round spermatids, pachytene piRNAs play a key role in regulating retrotransposon sequences through degrading the 3'UTR of retrotransposon mRNAs or recruiting factors such as DNMT3L to the retrotransposon sites.
After fertilization, there is a spike in retrotransposon expression when the genomes undergo reprogramming. Studies in mammalian models have demonstrated that piRNAs exist at various stages of early embryonic development and they may protect the embryo from these deleterious elements. They could protect the genome integrity through inducing de novo DNA methylation and epigenetic silencing of retroelements, preventing the action of various classes of repetitive and TEs at specific stages of embryogenesis. In addition, piRNAs could also ensure proper mRNA decay and patterning in the early embryos of Drosophila. Moreover, the initial steps of embryonic development depend on maternally loaded mRNAs and they are then massively degraded through the piRNA pathway to achieve the switches from the maternal to the zygotic genome.
| Evidence for Epigenetic Inheritance of Paternal Experience|| |
Accumulating epidemiological and observational studies evidenced that environmental exposures can influence male fertility and offspring health, ranging from flies to humans.,,, In the past decades, classic genetic studies highlighted that acquired characteristics affected by environmental exposures are closely associated with DNA mutations in sperm. However, the genetic mutation is slow and not a suitable mode for species to adapt to a constantly changing environment. Moreover, the vast majority of environmental factors cannot alter the DNA sequence, which makes it hard to predict the relationship between paternal exposures and male diseases as well as offspring health.
Epigenetic modifications are dynamic and sensitive to environmental exposures, which may be responsible for providing a potential mechanistic link between health conditions and environmental factors such as toxins, stress, and dietary factors.,,, Epigenetic pathways are essential for explaining the effects of environmental exposures on the health status, including DNA methylation, histone modifications, and noncoding RNAs. Several environmental exposures have been demonstrated to promote epigenetic profile alterations with implications for diseases. Large amounts of research have explored the effects of environmental factors on DNA methylation., Altered DNA methylation in specific genome regions has been observed with environmental toxins, nutrition abnormalities, and unhealthy lifestyles.,,, Moreover, altered DNA methylation could further induce abnormalities in chromatin structure and gene expression, finally resulting in environment-associated diseases. Furthermore, paternal exposure to environmental factors is responsible for defects of sperm and embryos, showing a potential transgenerational effect between generations., For example, male exposure to pesticides may increase the level of reactive oxygen species in testes, which has a severe impact on DNA methylation profiles in the sperm and this epigenetic alteration can survive multiple generations., Moreover, Wei et al. observed that paternal prediabetes may increase the susceptibility to diabetes in offspring via altered sperm DNA methylation patterns. The underlying mechanisms may be that the majority of locus-specific alterations could resist epigenetic reprogramming during embryogenesis, which has a potential effect on offspring health. In humans, the transmission of environmentally induced epigenetic information across generations is essential for explaining the relationship between food supply in ancestors and the offspring's health status. Kaati et al. demonstrated that paternal grandfather's exposure to a limited food supply during the prepubertal period could decrease the mortality rate of cardiovascular disease in the proband, while a surfeit food supply during the same period is closely associated with increased diabetes mortality in the proband and a shortening of the proband survival. Another convincing example of epigenetic inheritance is that Prader–Willi syndrome or Angelman syndrome is closely associated with the failure erasure of imprinting marks at the SNURF-SNRPN locus during spermatogenesis and the epimutations may derive from parental and grandparental chromosomal origin. Several studies have indicated that certain environmental factors could affect histone modifications and noncoding RNAs. Dashwood andHo showed that sulforaphane could inhibit HDAC activity and therefore increase histone acetylation levels at specific sites. Likewise, another study in mice observed that the level of H3K27me3 was lower at specific loci in males fed a low-protein diet. These findings indicate that histone modifications involve the mechanism of environmentally induced epigenetic inheritance across generations. In addition, noncoding RNAs can also contribute to the inheritance of environmentally induced epigenetic information. Recently, miRNA-375 has been shown to be linked to paternal stress, which is closely associated with depressive behaviors and impaired glucose metabolism in the offspring. More recently, data showed that a male mouse's high-fat diet or low-protein diet can alter metabolic gene expression in offspring, and the transfer RNA-derived small noncoding RNAs are epigenetic bridges for dietary regulation between generations., Consistent with this, Fullston et al. observed that obese males exhibited abnormal expression of 11 miRNAs in their sperm, by which they may pass on insulin resistance to the next two generations. In addition, Marczylo et al. found that 28 miRNAs were affected in the sperm of men by smoke, and that their expression patterns may persist for several generations. Taken together, these reports indicate that paternal environmental exposures could induce epigenetic alterations in sperm that further result in long-lasting effects on the offspring health.
As described above, it is apparent that sperm epigenetic profiles have a significant effect on early embryonic development. Therefore, the transmission of the environmental epigenetic information through sperm between generations is an intriguing topic. More and more evidences indicate that certain acquired phenotypes through environmental exposures can be inherited across multiple generations.,,,, One implication of altered epigenetics is that ancestors could transfer environmental information they experienced to their offspring in the absence of environmental factors. Therefore, the sperm play an important role in the transmission of altered epigenetic patterns to future embryos. This alteration in epigenetic patterns likely results in aberrant gene expression that may lead to altered phenotypes that is observed through multiple generations, indicating potential transgenerational effects.
Accumulating studies have evidenced the strong association between paternal experiences and the health status in the offspring. Moreover, sperm play a key role in the transgenerational inheritance of epigenetic information that responds to several types of environmental exposures. Nevertheless, the vast majority of specific epigenetic marks that are responsible for the transmission of environmental information across generations remain unclear. In addition, the truly transgenerational epigenetic effects should be examined on the third or later generations., Therefore, the direct epigenetic effects on human sperm and the offspring's health are relatively sparse. Satisfyingly, several studies have demonstrated that grandmother's exposure to pesticides, bisphenol A, or dioxin during the gestational period could result in abnormal phenotypes and aberrant sperm epigenetic patterns in the F3 generation.,, Analysis of epigenetic profiles and long-term follow-up studies via interdisciplinary research are essential for elucidating the transgenerational epigenetic effects resulting from environmental exposures.
| Windows of Susceptibility for Environmental Exposures|| |
A great number of studies have demonstrated that environmental exposures play an important role in the accumulation of epigenetic patterns at specific loci, which further affects normal development and even causes various diseases via tightly regulated gene expression at the epigenetic level.,, The idea that epigenetic alterations could result in diseases without any changes in genetics provides a possible mechanism for epigenetic transmission. Therefore, the crucial question is how and when the environmental epigenetic information is transmitted between generations. During spermatogenesis and early embryogenesis, two waves of epigenetic reprogramming occur, which represents four windows of susceptibility to environmental factors with the erasure and reestablishment of epigenetic marks. During the period of four windows, epigenetic modifications show a striking variation in profiles, which makes them particularly vulnerable to environmental factors.
The most sensitive window is represented during embryonic development, when PGCs migrate to the genital ridge. During the period of PGCs' development, the germline epigenome undergoes a dramatic genome-wide erasure. This provides a crucial window of sensitivity to environmental exposures. Consistent with this information, environmentally induced epigenetic alterations in the germline can be transmitted across generations.,, The second window is represented at paternal prepuberty; reestablishment of epigenetic marks occurs with sex-specific steps mainly during germline development, which provides another sensitive window for environmental exposures on the germline epigenome. The environmental exposures to vinclozolin at the time when male PGCs are undergoing reestablishment of their epigenome may lead to altered somatic cell gene expression and development of adult-onset disease.,, This study indicates that environmental exposure can affect the offspring's health status via an altered germline epigenome., The third window can be identified at the period of spermatogenesis; it appears to be necessary for the prevention of environmental exposures and could be used as a preventive strategy. During spermatogenesis, epigenetic patterns, DNA methylation for instance, are gradually reestablished., It has been demonstrated that the transcriptional activity of DNMT is dynamic and thus vulnerable to environmental exposures. It has further been demonstrated that estrogen, a type of obesity-related hormone, could accumulate in scrotal fat, potentially affecting sperm genomic imprinting. The underlying mechanism is that the estrogen receptor β interacts with DNMT1 and binds an estrogen response element at the H19 DMR, catalyzing methylation of the H19 CpG island. These studies support the idea that environmental estrogens may disturb a normal crosstalk between estrogen signaling and imprinting during spermatogenesis. Finally, the fourth window is represented at the zygote stage. After fertilization, epigenetic modifications are all reset to establish a proper epigenetic landscape in early embryos, which involves DNA demethylation, protamine to histone replacement, and changes in RNA profiles. The erasure of epigenetic marks during this period makes the embryo's epigenome vulnerable to environmental exposures. Therefore, we define the zygote stage as the fourth sensitive window where paternal effects may play an indirect role.
| The Survival Mechanisms for Environmentally Induced Epigenetic Information throughout Reprogramming|| |
Epigenetic modifications are critical mediators to gene expression and therefore development in spermatogenesis and embryogenesis. Nearly each cell type has its unique and stable epigenetic profiles. In addition, the epigenome is also required to be reset during spermatogenesis and early embryogenesis to acquire developmental pluripotency, which makes the developing epigenetic patterns susceptible to environmental exposures.,, Increasing evidences indicate that epigenetic alterations are closely linked to environmental factors, which provides a potential mechanism by which environmentally induced epigenetic changes can have long-term effects on the offspring's health. Moreover, several reports suggest that environmental information does reside in sperm epigenetic carriers and can affect the offspring's phenotypes via transgenerational effects. However, a central challenge to transgenerational epigenetic inheritance is the reprogramming of epigenetic profiles across generations that all seem aimed at erasing the epigenetic memory of their parent of origin, giving rise to a totipotent embryo. The controversy on the study of environmentally induced transgenerational epigenetic transmission suggests that other modes of inheritance might play a pivotal role in the survival of environmental information between generations. Several epigenetic mechanisms including DNA methylation, histone modifications, and ncRNAs are discussed to explain how these epigenetic marks escape from the genome-wide epigenetic reprogramming.
DNA methylation is the first sensitive mark to environmental exposures, which places it as an excellent candidate for serving as a transgenerational epigenetic mark.,, However, there are two main processes for the reprogramming of DNA methylation during the development of PGCs and early embryos, which makes it impossible to evoke the transgenerational effects via DNA methylation marks., Interestingly, some portions of the particular repetitive sequences, such as intracisternal A particle elements, LTR-ERV1 elements, and a few single-copy sequences, have been reported to have DNA methylation that could escape erasure, which opens the potential for transgenerational inheritance of DNA methylation passing to the offspring.,, In addition, the DNA methylation that regulates some imprinted loci has been found to show environmentally sensitive variations and resist the global demethylation in the preimplantation embryo, which establishes the principle of environmentally induced transgenerational inheritance.,,, The survival mechanisms by which imprinted loci can escape the erasure of DNA methylation are that the maternal factor PGC7 could maintain methylation status at the imprinted loci via binding H3K9me2 and inactivating TET3. Moreover, Messerschmidt has suggested that DNA-binding factor Zfp57, together with Kap1 and H3K9me3, is essential for the maintenance of paternal imprints. Furthermore, some nonimprinted sequences escape erasure as well and play a key role in bearing transgenerational inheritance of DNA methylation., Increasing evidences suggest that a small fraction of repeat-based TEs could escape demethylation during PGCs' differentiation., It is important to note that many nonimprinted, nonrepetitive genomic loci remain subject to epigenetic control in sperm.
Histone modifications have been shown to be closely linked to environmental exposures, which can be transmitted from sperm to zygote and regulate early embryonic development, thereby affecting the offspring's phenotypes., During spermiogenesis, the majority of histones are replaced by protamines and only a small fraction of histones retain in sperm and is transmitted to early embryos, which complicates the mechanisms for the survival of histone modifications across generations. Therefore, the retained histone modifications are the most promising candidates for the transmission of paternal epigenetic information. It is important to note that histone retention at CpG-rich sequences lacks DNA methylation, which might serve as a mediator for shaping certain phenotypes in the offspring.,, For example, the H3K4me3 appears to regulate gene expression during early embryogenesis. In addition, H3K27me3 in sperm may persist in the zygote and show repression in the preimplantation embryo., Furthermore, Carone et al. found that paternal diet could affect H3K27me3 status in sperm, indicating that histones in the sperm may acquire and retain signatures of environmental exposures. Moreover, H3K4me3 and H3K27me3 are bivalent marks that can co-occur at specific loci, which provide a viable platform for the transmission of environmental epigenetic information across generations.,, The underlying mechanisms for the inheritance of histone modifications likely involve a combination of histone chaperones. For example, HIRA is a H3.3-specific chaperone that may deposit histone H3.3 at destabilized nucleosomes or transcriptional start sites, which also promotes the replacement of protamines after fertilization. This event is essential for heterochromatin establishment and facilitates the survival of epigenetic information during dramatic reprogramming.
A great number of reports have demonstrated that sperm-derived ncRNAs play a pivotal role in regulating paternal transgenerational epigenetic inheritance.,,,, miRNAs and piRNAs, for instance, can result in decreased gene expression at the posttranscriptional level. In addition, they also play an epigenetic role via targeting specific sites for either DNA methylation or histone modifications. The susceptibility to environmental exposures positions ncRNAs as sound candidates for the inheritance of environmental information. For example, diet-induced paternal obesity in mice could alter sperm miRNA profiles that can be transmitted to subsequent generations and affect metabolic functions in offspring. The question is how ncRNAs survive from epigenetic reprogramming and persist through multiple generations? The amplification is essential for ncRNAs against the dilution effect. In addition, the transgenerational effects of ncRNAs are regulated by heritable RNAi defective-1 (HRDE-1) and the nuclear RNAi-defective (NRDE) factors. Both HRDE-1 and NRDE proteins might function in promoting transgenerational ncRNA effects rather than in shuttling the heritable ncRNAs between generations.
| The Prevention of Environment-Associated Epigenetic Disorders|| |
As described above, environmentally induced epigenetic mark changes in sperm could survive epigenetic reprogramming and can be transmitted to offspring for several generations. It is important to note that the potential carriers such as DNA methylation, histone modifications, and noncoding RNAs play essential roles in the transmission of environmental information across generations. The transmission of environmental information through sperm epigenomes provides a window for explaining the transgenerational inheritance of acquired characteristics. For example, the altered sperm DNA methylation patterns induced by dichlorodiphenyltrichloroethane (DDT) could be detected in the F3 sperm generation. The transgenerational inheritance of these sperm epimutations requires the transmission of the DNA methylation in low CpG density. DDT induced a unique set of epimutations enriched in the areas of low CpG density that may be especially important for gene regulation. It is, therefore, not surprising that the DNA methylation patterns in low CpG density may be a component of sperm DNA methylation profiles for the DDT F3 generations. In addition, prediabetes in fathers increases the susceptibility to diabetes in offspring via altered sperm epigenomes. Besides metabolic diseases, epigenomic alterations have been linked to many cancers in humans. In some cases, DNA methylation changes in MLH1 and MSH2 are involved in human colorectal cancers, and environmental epigenetic inheritance through sperm has been proposed as one explanation for the inheritance of this disease.,, Collectively, these facts imply that epigenetic inheritance through sperm may increase the risk for susceptibility to these chronic diseases in offspring.
As indicated above, environmental epigenomics in sperm is very important in determining the health status of offspring. Moreover, the altered sperm epigenetic patterns appear to be unique to the specific environmental exposure. Therefore, identification of epigenetic marks in sperm is a potential strategy to predict the risk for epigenetic-associated diseases in offspring and provide certain therapeutic targets for the treatment of these diseases. To achieve this goal, genome-wide epigenetic analysis via specific high-throughput techniques will be very helpful to detect specific environmental epigenetic markers. Moreover, bioinformatic methods are critical to process the huge amounts of data efficiently, which significantly improves our understanding of sperm epigenetic marks and their role in early embryonic development. In addition, single-cell sequencing technique has recently been applied for the analysis of sperm and early embryonic epigenetic profiles, which is essential for the birth of a healthy baby. Most importantly, further studies of epigenetic biomarkers in sperm are necessary for us to select high-quality sperm to avoid certain diseases caused by epigenetic aberrations. It is important to note that a great number of studies in this field are the prerequisite to improve the diagnosis and prevention of transgenerational epigenetic diseases.
| Conclusions|| |
A great number of reports provided evidence that sperm equipped with specific epigenetic patterns play a key role in initiating early embryonic development.,,, The potential epigenetic carriers including DNA methylation, histone modifications, and noncoding RNAs are essential for the transmission of sperm epigenomes to the zygote. It is, therefore, becoming clear that paternal environmental exposures can alter the sperm epigenetic profiles that may survive epigenetic reprogramming and inherit across generations, ultimately resulting in different chronic diseases in the offspring. However, the environmental epigenetic changes may accumulate but the threshold for environmental epigenetic inheritance is not known. Moreover, the underlying mechanisms for the survival of environmental information during epigenetic reprogramming remain largely unknown. Therefore, future scientific research is necessary to elucidate the potential mechanistic relationships between environmental exposures and disturbances in epigenetic patterns. Furthermore, research on the investigations of multiple generations is essential for better understanding of the survival mechanisms underlying transgenerational environmental effects through the reprogramming processes. In addition, identification of the environmentally induced epigenetic markers in sperm may provide a better understanding of the etiology of certain chronic diseases in offspring, which is essential for determining the risk for susceptibility to specific diseases in offspring and developing novel diagnostics and therapeutics for the treatment of specific diseases.
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