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Methylation of DNA is already known to be very important; for example extreme cases of demethylation, representing a loss of gene expression control, are associated with oncogenesis Feinberg and Tycko, Before we can fully grasp the effects epigenetics has had on our species a firmer understanding of what epigenetics is and the way in which it can alter gene expression is needed.

Gene control is a fascinating area of genetics and this is particularly interesting to those with a fascination for human evolution. Epigenetic influence over gene expression possibly originated as a defence against Transposons, parasitic DNA that jumps around in the genome and can disrupt genes by inserting into the middle of them Slotkin and Martienssen, A possible mechanism of defence can be achieved via methylation of DNA, as illustrated in Fig.

Eventually this process evolved into a method of promoting and repressing host genes Feinberg, that could not only be acquired throughout the lifetime of an individual, but also passed onto its offspring Jones, This mechanism of gene silencing may have also allowed for the development of multicellular organisms by allowing a single genome to tailor its expressed genes in each individual cell within the larger organism Badyaev, Methylation as a defence against Transposons. The figure illustrates how methylation can help an organism defend itself from Transposons.

While epigenetics is a relatively new understanding of the systems involved in gene control and expression it also represents something very important, a fundamental revaluation of the theory of evolution. Acquired traits, while not alterations of the genome, can be inherited Jones, This review will examine the implications this has for the concept of human evolution and highlight interesting examples and case studies in which these effects are notable.

The study of epigenetics has revealed an interesting facet of this method of gene expression control. The methylation of DNA and other epigenetic marks do not alter the genes that they influence at a sequence level but nonetheless alter the expression of these genes.

Furthermore these marks can be acquired throughout the lifetime of the individual and, if carried in their gametes, these marks are inheritable. In this section, the focus will be on the ways in which these marks can be inherited. The semi-conserved nature of mitosis results in two sets of daughter chromatids, one in each set carrying the Epigenetic marks from the original chromosome Feinberg, , as illustrated in Fig.

This allows the transfer of epigenetic marks from mother cells to daughter cells in somatic tissue. This explains how these marks can be maintained in an individual, but not how they are spread to the next generation of offspring. As can be seen in A the original chromosome contains epigenetic marks on both chromatids, and in B both daughter chromosomes contain some of the epigenetic marks of the mother chromosome due to the semi-conserved nature of mitosis.

These marks can also be conserved in their daughter chromatid during meiosis, resulting in all gametes carrying the epigenetic marks of the individual of origin. However, many of these marks are removed during the process of gamete formation. Methylation marks can be inherited from either the maternal Giuliani et al.

Through the father, the offspring can inherit a wide array of methylation marks, with the majority of these marks in some way affecting the digestive systems of the child Soubry, For an example of this deleterious nature of hypomethylation one can look at the Dutch Winter of Hunger, a well-documented example of famine in the modern world that occurred from to due to a blockage preventing the movement of fuel and food in the Netherlands.

This starvation resulted in the hypomethylation of the IGF-2 gene, the gene responsible for the formation of insulin-like growth factor 2. The ability of parental malnutrition to affect the epigenome of the offspring in an overtly negative and harmful way will be examined more closely later in the review. This was very useful and advantageous for nomadic peoples and a case study of this can be seen in the comparison of the Oromo peoples and the Amhara peoples of Ethiopia Alkorta-Aranburu et al.

In this case it appears that epigenetic marks actual favour immunological variation within the newly arrived population. This will be examined in more depth as part of the Case studies section later in the review. This will eventually result in a population that is genetically similar to the original settlers but will be more adapted to their surrounding environment. To understand the impact epigenetics has had on our development into modern humans we have to compare the areas of gene methylation seen in our species and our closest living relatives.

Many of the regions in the human genome that are methylated are not genes that are unique to humans, with the biggest differences in methylation occurring in regions of DNA involved with Transcription Factors or TFs and gene control Hernando-Herraez et al. This is because TFs have a wide-reaching influence on the expressed phenotype of an individual due to these factors functioning as a form of gene expression regulation, therefore promoting or suppressing other genes in the genome.

Even small differences in the epigenome surrounding TFs can result in widely varying phenotypes between individuals of the same species due to their wide-reaching influences Heyn et al. So it can only be assumed just how important these phenotypic changes are in the variation that separates us from our ancestor species. HARs are regions of DNA that have undergone rapid changes since the emergence of the human species far and above the normal rate of mutation. These regions stand out due to the extremely accelerated rate of mutations they have undergone and are widely understood to be responsible for the speedy divergence of humans from other species Hubisz and Pollard, The exact nature of the role played by epigenetic changes in HARs is not clear but the importance of their role is undoubtable, with epigenetic changes possibly predating sequential changes in DNA Badyaev, A suggested theory is that these marks actually promoted the occurrence of mutations in the genes that are responsible for our species existence.

Studying the epigenomes of our related species sheds light on the relatively large divergence that has occurred since our emergence from our distant cousins, a divergence of such stature that it cannot be solely explained by nucleotide changes Hernando-Herraez et al. It has even been speculated that epigenetic changes could be more impactful on the Darwinian evolution of a species than genomic mutations Badyaev, and this area of research only adds more weight to these claims. Modern humans have survived and thrived in a wide array of environments for thousands of years, from the Arctic tundra to Saharan deserts.

The key to this success has always been the uniquely human ability to adapt quickly and epigenetics has played a role in this capacity to adapt. While cultural adaptations to environments, such as changes in clothing or ritualistic behaviour, are the most visual signs of this adaptability, no less important are the more subtle genetic and epigenetic changes that a population undergoes as they live in an area for generations.

For example a population that has lived in an arid environment will carry many genetic mutations that make them more suitable to a dry climate. If a catastrophic climate shift occurs and their ancestral lands suddenly become cold and damp they can adapt to wear thicker clothing Cavalli-Sforza and Feldman, to protect against the cold and may even take on new customs and rituals around hygienic behaviour to protect against new diseases that have taken root in the region Wiesenfeld, This population will however still carry many of the genetic mutations that made them suited to their old environment until selection pressure allows new mutations to compensate for these genetic relics.

An important idea is the way in which to consider each different type of adaptation in comparison to one another. Cultural adaptation is a catch all term that encompasses all artificial adaptations an individual can pick up to become more comfortable in an environment Cavalli-Sforza and Feldman, In comparison genetic changes, such as the prevalence of Sickle Cell Anaemia in regions prone to malaria outbreaks, represent much longer term adaptations.

These changes take longer to gain and cannot as easily be shaken off once their usefulness has run its course, such as an individual simply changing their attire to suit the weather Laland, Odling-Smee, and Myles, What do epigenetic changes represent in this model then? Firstly they exemplify medium-term adaptations, falling between cultural changes and genetic evolution in the time it takes an individual to acquire them Giuliani et al. In this model of understanding human adaptation epigenetic changes also serve as a time-keeping mechanism, helping to mitigate the negative effects of genetic relics acquired by ancestor populations under different evolutionary pressures Badyaev, By silencing older genes that once served a vital purpose epigenetics also helps to prevent the build-up of complexity in an organism, silencing older, less frequently transcribed genes Badyaev, , much in the same way that DNA methylation combats the damage caused by transposons Slotkin and Martienssen, A good way to examine this model of adaptation is to consider the way each of these changes would affect a hypothetical population that has suddenly become exposed to a harsh, cold climate.

Very quickly, this population will adapt, first by increasing their protection against the elements by wearing thicker clothes. While this is an effective method of staying warm their bodies have not yet adapted to the cold, and so, their genes controlling homoeostasis will still function in the same way as they had in a warmer climate, something that might be considerably wasteful and possibly deleterious. Where once their perspiration would help keep the heat from damaging their bodies it now wastes water.

At this stage, after a considerable number of generations, epigenetic changes will begin to take affect under selective pressure. DNA methylations and histone modifications will accumulate, fine tuning their homoeostatic gene expression to the colder environment.

This results in the silencing of genes that were better suited to the hotter climate and promotes the expression of other genes that confer an advantage in this colder one. Finally, after even more generations new alleles will take hold in the populations that represent novel genes. These novel genes will encode new proteins that in some way will provide a selective advantage that is near permanent in expression, if not in providing an advantage.

Another point highlighted by this model is that the longer an adaptation takes to be acquired the less likely it is to ever be lost. After all, it is much easier to take a jacket off than to spontaneously lose a gene responsible for increasing metabolic activity. Epigenetics comes in yet again at this point as not only does it silence older genes that are no longer required, under the influence of selective pressure, it also introduces more plasticity into the expression of genes Giuliani et al.

Through this mechanism epigenetics allows the variability of phenotypes that are required for adaptation and selection Tobi et al. An interesting examination of epigenetics that provides an example of its role in human evolution is a study into the different epigenetic markers between the Oromo and Amhara peoples of the Ethiopian highlands, which revealed something surprising: researchers expected to find that individuals of the Oromo peoples, who are migrants to the highlands, would have an increase in epigenetic marks around genes associated with oxygen uptake or red blood cell production.

These are adaptations that the Amhara peoples already had, allowing them to live successfully in their elevated homeland. Instead many of the epigenetic markers the researchers found in the Oromo population were around genes associated with the immune system Alkorta-Aranburu et al. More interesting was that these marks were not uniform throughout the population and instead varied widely from person to person Alkorta-Aranburu et al.

This appears to show epigenetic marks acting as a catalyst for the introduction of variation in gene expression, resulting in a wide range of phenotypes and responses to combat the new microbiological threats that the migrating population were exposed to upon arriving in the region. Here, these epigenetic marks are compensating for the lack of immunological adaptation the Oromo peoples have for this new climate compared to the native Amhara people, mitigating the damage done to the Oromo populations in the interim before a genetic mutation could occur that provides stronger protection.

As discussed earlier epigenetics plays a key role in the dietary adaptation individuals carry, producing an individual who carries epigenetic marks that make them more suited to the diet of their parents. Lactose tolerance is one of the ways this epigenetic digestive adaptation manifests Ingram et al.

With the increasing availability of dairy products worldwide, the epigenetic modification that produces a weaker tolerance to lactose can only be expected to increase, at least until the lactose tolerance mutation proliferates into the global gene pool. Various genetic conditions affect red blood cells and their ability to uptake oxygen. These include Sickle Cell Anaemia and Thalassaemia, both of which only occur once the switch to adult haemoglobin is complete in an individual Sripichai et al.

In the case of Sickle Cell Anaemia it is known that the condition confers a resistance to Malaria. With anti-Malaria treatments becoming more and more efficient and mosquito culling beginning to keep infection rates under control it has become a condition that now mostly serves to burden fledgling health services around the world. As the selective pressure on these populations has changed, the epigenome of these populations has also reacted.

POFH is a condition where an individual never undergoes the switch to adult haemoglobin, and thus avoids expressing the Sickle Cell Anaemia and Thalassaemia mutations. While they still carry these mutations these individuals do not express the deleterious phenotypes due to epigenetic markers that inhibit the associated genes. This is illustrated in Fig.

A shows what occurs in an individual who carries the mutations but does not have any epigenetic marks silencing the Adult Haemoglobin Switch Gene. These individuals will eventually develop Sickle Cell Anaemia. In B the Adult Haemoglobin Switch Gene is silenced by epigenetic marks, and as such the Sickle Cell Anaemia gene is never expressed as the individual maintains production of Foetal Haemoglobin.

Throughout this review changes to the epigenome of an individual have been discussed in an overly positive light. Such changes can be a mechanism that provides a quicker form of adaptation than genetic mutations Giuliani et al. It can also act as a time-keeping mechanism in older and now deleterious genes Badyaev, Lastly it can be an influential response to Darwinian pressures on an individual or population Alkorta-Aranburu et al. For example, there is a known link between hyper-demethylation and oncogenesis Feinberg and Tycko, , but this review will consider the negative aspects of epigenome changes in terms of its impact on human evolution.

Epigenetics can act as a time-keeping mechanism by silencing genes that have outlived their purpose. However it is worth noting that this function of epigenetic marks has limits, as in many cases the gene in question is not entirely silenced Badyaev, , but instead is expressed at a lower rate. From a Darwinian perspective this is an undesirable consequence as the individual will survive but their offspring will instead now possess a trait that reduces their adaptability. In this way many traits that lower the overall fitness of the species may accumulate.

The role epigenetics plays in digestive adaptation also comes as a double-edged sword. In this view, it is possible to hypothesize that an alteration of the correct distribution of nucleosome retention within sperm DNA could produce an impairment of embryo development. As a matter of fact, Hammoud et al.

Phenotypic plasticity and the epigenetics of human disease.

Moreover, genes in histone-bound regions appear more susceptible to DNA damage induced by smoking, obesity, and aging as compared to protamine-bound regions, due to the incapacity of sperm to repair DNA damage [ ]. Thus, the reported data above suggest that, in some instances, epigenetic defects of the sperm could induce not only a poor sperm quality, but also a decreased ability of development of the generated embryo after the fusion of the gametes, providing a possible explanation for a number of early pregnancy loss after both in vivo and in vitro fertilization.

A large amount of literature data, including human and animal studies, has raised concerns about an increased risk of different diseases in the offspring generated by the use of ART [ , ]. Several evidences have suggested that the majority of these abnormal conditions are related to epigenetic alterations.

Early studies carried out in mice had showed that alterations affecting the development and growth of the fetuses were linked to ovulation induction, manipulation of eggs, or embryo culture in vitro [ — ]. A confirmation came from Khosla et al.

Moving to different animal models, Young et al. Subsequently, the pathogenesis of LOS was suggested to be associated with epigenetic abnormalities, leading to loss of imprinting and over-expression of IGF2 receptor gene [ , ]. Factors in the ART procedures, triggering these imprinting errors, were not clearly identified, but the onset of the syndrome appeared to be dependent by in vitro culture conditions [ , ]. In human, a larger prevalence of syndromes related to imprinting alteration, particularly Beckwith-Wiedemann and Angelman syndromes, has been reported in children born after ART when compared to non-ART children [ — ].

Interestingly, the phenotype of Beckwith-Wiedemann syndrome, an overgrowth condition characterized by large size at birth, macroglossia, and visceromegaly, closely remembers the previously described LOS in cows and sheep generated by in vitro fertilization, suggesting a common mechanism of origin of these conditions. On the other hand, also a disproportionate number of low birth weight cases has been observed in ART children [ ]. The association between ART and altered DNA epigenetic profiling has been demonstrated also by studies based on the analysis of the methylation status of CpG sites in the promoters of genes of placenta and cord blood obtained from children conceived in vitro and in vivo [ ].

This analysis showed hypomethylation of most CpG sites in the placenta and hypermethylation of most CpG sites in cord blood in the group of children conceived by in vitro fertilization as compared to naturally conceived children. Interestingly, the genes showing different expressions in the two groups appeared to be involved in chronic metabolic disorders including obesity, type II diabetes, and high blood pressure [ ].

These data are in agreement with other studies reporting an increased risk of disturbs in body fat composition, changes in blood pressure, and increase in the late infancy growth velocity in children generated by ART procedures as compared to control children [ — ]. In addition, other studies showed a high risk of obesity or type II diabetes in adult life in children generated by ART [ ]. These results strongly suggest that the effect of ART procedures could be manifested not only at birth, but also in late infancy or even in adult life.

As in animal models, the in vitro culture conditions have been suggested as a main cause of epigenetic defects in the offspring generated by ART also in human [ ]. In addition, it has been proposed that the low birth weight observed after ART, as well as in small for gestational age and very premature children, is the result of an unfavorable embryonic, fetal, or neonatal environment, involving also epigenetic mechanisms, potentially related to metabolic alterations in late childhood [ ]. However, several evidences have suggested that a crucial role could be also played by epigenetic defects in the sperms used in ART protocols.

In fact, several authors suggested that DNA methylation changes at imprinted loci are inherited from the sperm of men with oligozoospermia [ 82 , , ]. This could suggest that the increase of DNA methylation variations in ART depends, at least in part, on the presence of epigenetic defects of male gamete.

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In this view, some authors have proposed the possible usefulness of analyzing the imprinting methylation status in the routine sperm examination for ART treatment [ ]. Unfortunately, this argument remains poorly understood, as demonstrated by other studies reporting that epigenetic abnormalities detected in sperms of oligozoospermic patients do not appear to be associated with ART outcome, suggesting that further studies are required in order to shed light on the relationship between sperm epimutation and alterations in children generated by ART [ ].

Several environmental and lifestyle factors stress, physical activity, alcohol intake, smoke, shift work are known to affect male and female fertility [ ], and in many cases, they have been shown to influence the occurrence of epigenetic modifications with implications for human diseases [ ]. The presence of an environmental epigenetic inheritance through gametes has been evidenced by studies carried out on different animal models [ ]. A few studies have suggested that food or physical activity can influence histone modifications and miRNA expression.

Dashwood et al. Anyway, the largest body of evidence comes from studies investigating the environmental effects on DNA methylation. Further information in this field has been provided by studies investigating the role played by paternal exposures to various pollutants and lifestyle-related conditions on the health status of the offspring and of the future generations.

Great attention has been devoted to the effects of paternal exposures to environmental toxins or low-dose ionizing radiation, and of paternal lifestyle [ ]. Several studies had previously demonstrated the presence of a strong association between paternal occupational exposures to chemicals and harmful health outcomes in the offspring. Feychting at al. Reid et al. However, many of these conditions are likely related to the presence of mutations in sperm DNA, thus representing a genetic, rather than epigenetic, mechanism.

Is there any evidence supporting the presence of epigenetic mechanism driving the effects to the offspring of the paternal exposure to chemicals? Once again, the most relevant data in support of this hypothesis come from studies on animal models, showing that male exposure to pesticides or other harmful chemicals can be responsible for defects in the gametes and abnormal development of the offspring mainly via altered DNA methylation patterns in the germ line [ , ].

Anway et al. Similar results were obtained by Guerrero-Bosagna et al. Also, ionizing radiations have been recently invoked as a risk factor for alterations of DNA methylation. These radiations trigger a series of processes on the cells as genotoxic alterations including DNA breaks, but the actual mechanism leading to a transgenerational effect is still poorly understood. Dubrova et al. These authors suggested that the persistence of instability into the germ line of unexposed offspring of irradiated mice could be responsible of mosaicism in germ cells, a well-known mechanism in the origin of human genetic disorders [ ].

More recently, it has been suggested that a crucial role in transgenerational radiation effects, such as genomic and epigenomic instability, could be played by the Piwi-interacting RNAs piRNA pathway, involved in the maintenance of genomic stability by facilitating DNA methylation of transposable elements and also implicated in other epigenetic alterations affecting a variety of cellular regulation processes [ ].

Another experiment on animal models supports transgenerational epigenetic changes as a result of parental exposure to genotoxic stressors, as irradiation, nutrition, and intake of anti-androgen compounds [ ]. For example, it has been demonstrated that treatment with the anti-androgen compound vinclozolin on female mice induces epigenetic effects in the sperm of their offspring as compared to controls [ ].

One of the most intriguing topics in the field of epigenetic modifications of the germ line is represented by the influence played by the paternal diet on gametogenesis. The first evidences of this association came from animal models. Carone et al.

Why Parents Matter (Epigenetically): Genomic Imprinting in Health and Disease

Based on these results, authors suggested that cholesterol and lipid metabolism in an offspring can be strongly affected by paternal diet [ ]. This study was carried out by a whole-genome characterization of cytosine methylation patterns and RNA content in sperm obtained from mice submitted to low-protein or caloric restriction diets and controls. Authors detected similar cytosine methylation patterns in all three conditions, thus suggesting that the sperm epigenome is largely unaffected by these diets and that changes in relatively few loci can have profound effects in the developing animal [ ].

However, in a more recent study, Radford et al. In another animal study, Ng et al. This effect was mediated by the altered expression in adult female offspring of pancreatic islet genes, belonging to 13 functional clusters, including cation and ATP binding, and cytoskeleton and intracellular transport.

Fullston et al. In addition to experimental data on animal models, very interesting data about the role played by diet on the epigenetic modifications and on the consequent transgenerational effects are available in human as well. During the winter of —45 of World War II, in the Netherlands, as a reprisal against the activity of the Dutch government-in-exile aimed to disrupt the transport of German reinforcements and troops, the Germans banned all food and fuel transports to Netherlands, inducing a severe famine, with the official daily rations for the general adult population decreasing gradually from about calories December to below calories April The situation improved in a very short time after the liberation of the Netherlands on May , with the rations raising up to over calories a day by June [ ].

The famine caused a severe mortality in the population of Amsterdam, but nevertheless, several babies were conceived and birthed during that period. Several decades later, a number of studies investigated the health status of people born in Amsterdam during the famine period in order to shed light on the effects of malnutrition on the health of the offspring in adult life. In a first time, these studies evidenced an association with chronic diseases in adult life in the offspring coronary heart disease, atherogenic lipid profile, obesity, raised levels of plasma fibrinogen, and decreased levels of factor VII , strongly related to the timing in gestation of exposure to famine [ , ].

However, by analyzing the results of these epidemiological studies with the aid of molecular tools, it has become clear that the Dutch famine families study has provided the first direct evidence for epigenetic programming through prenatal famine exposure. In fact, it was clearly demonstrated that periconceptional exposure to famine produced an under-methylation likely related to a deficiency in methyl donors in the differentially methylated region DMR of the maternally imprinted IGF2 gene [ ], suggesting that early undernutrition can cause epigenetic changes persisting throughout life.

On the other hand, there was no variation in IGF2 methylation status in individuals exposed to famine in later gestation. Further studies evidenced that persistent changes in DNA methylation represent a common consequence of prenatal famine exposure and that they can be affected by the sex of the exposed individual and the gestational timing of the exposure [ ]. More recently, it has been demonstrated that prenatal malnutrition-associated DMRs P-DMRs mostly occur in regulatory regions of genes showing differential expression during early development [ ]. All the above-reported studies suggest that undernutrition plays a direct effect on the fetus during the early phases of development.

However, why should we exclude that the target of the famine could be represented also by gametes other than by embryo? Several evidences strongly suggest a role played by paternal diet on the healthy status of children, as confirmed by the above-described results on animal models. Soubry et al. In particular, the significant association between paternal obesity and altered methylation in the offspring suggests the susceptibility of the developing sperm to environmental insults.

Despite these limitations, the possible presence of transgenerational effects related to the epigenetic effect of paternal diet remains a very interesting topic. A crucial question concerning the role played by environmental agents in the epigenetic modifications of the male gamete is the following: when are the effects of such exposures transferred to the male gamete? The first window is represented by paternal embryonic development, when PGC undergo genome-wide epigenetic erasure during migration to the genital ridge.

Defects in this process, as well as in the maintenance of some protected regions, could be caused by internal or external factors during early development. The second window is represented by paternal prepuberty, since in this period, de novo methylation at imprinted gene loci occurs. The third window can be identified in the period in which spermatogenesis, and in particular the development from spermatogonium to spermatocytes, occurs, since methylation patterns are established during this time. This window appears to be a very important one, representing the reproductive period of the subject, when a careful evaluation of his lifestyle, with prevention of environmental stressors, could be used as a preventive strategy.

Finally, the fourth window is represented by the periconception period and the zygote stage, when histone retention in certain genes could represent a potential mechanism for inheritance of environmentally induced epigenetic marks. While studies investigating the effect of environmental agents in the latter three windows are currently carried out, mostly on animal models but also in humans, it is more difficult to investigate epigenetic modifications in PGCs.

However, the recently reported discovery that amniotic fluid stem cells AFSCs share a number of features with PGCs [ ] provides a novel cellular model for the study of the effect played by environmental agents in altering the epigenetic processes occurring in these cells, opening new scenarios in this field of study. Finally, it must be stressed that aging represents another possible risk factor for epigenetic modifications increasing the risk of neuropsychiatric disorders such as autism and schizophrenia. Jenkins et al. These authors evidenced that a portion of the age-related changes in sperm DNA methylation involves genes previously associated with schizophrenia and bipolar disorder.

As evidenced by the large amount of studies carried out in this field, epigenetic mechanisms play a key role in the proper function of the male gamete, and alterations in these mechanisms can widely affect human reproduction. The effect of epigenetic modification of sperm gene function can affect the reproductive outcome in at least four different levels: 1 impairment of male fertility due to alterations in sperm number and morphology; 2 alterations of embryo development; 3 poor outcome of the ART protocols; and 4 risk of pathologies in the adultness for the offspring Fig.

Due to the huge interest devoted to this topic by the scientific community, related to the possible implications in the field of human reproduction and health, our knowledge about the above-discussed mechanisms are increasing day by day. Recent studies have highlighted the molecular mechanisms underlying the epigenetic transgenerational inheritance of some disease. Guerrero-Bosagna et al. Epigenetic alterations induced by lifestyle and environmental factors diet, smoking, radiation, alcohol consumption, etc. As a first consequence, these modifications can induce sperm alterations leading to impairment of male fertility.

When fertilization occurs, spontaneously or by ART, transgenerational epigenetic effects can be observed, in details leading to 1 alterations of embryo development, 2 congenital diseases at birth, and 3 late onset diseases obesity, hypertension, diabetes, etc. It can be suggested that in the next future, the study of epigenetics and epigenomics will likely represent a crucial step in the diagnostic workup of the infertile male, especially in cases submitted to ART, where it will be necessary to select adequately functional sperm to avoid the epigenetic alteration impact on the procedure.

So far, the application of the analysis of epimutations in the male gamete in the clinical practice is hampered by the lack of complete information about the involved genes and by the use of expensive, low-throughput techniques. However, due to the large number of ongoing studies in this field, a clearer picture of the situation should be available in a short time, and the set-up of specific assays will likely reduce the costs and the time of these analyses. Further information will likely be provided by studies investigating the role played by sperm non-coding RNA in male fertility, which represents a very promising field of study [ ].

Another very exciting field is represented by the potential role played by the non-sperm fraction of the seminal fluid, since postejaculatory effects on sperm survival and functional competence have been reported [ ]. Surprisingly, seminal plasma may affect offspring independently of sperm, by stimulating the production of embryotrophic cytokines and growth factors by the female reproductive tract [ ].

The alteration of this process induces abnormal fat deposition and metabolic phenotype in the offspring, particularly in the males [ ]. Finally, great attention should be devoted to the role played by environmental agents both in determining and in repairing epigenetic alterations.

Most importantly, the possibility that paternal lifestyle could affect the health of the offspring during lifetime opens a novel and exacting scenario in the prevention of common, late onset diseases [ ]. This work was supported by grants form the G. Competing interests. LS and MF carried out the search of literature about epigenetics and male infertility, epigenetics and ART, and environmental factors inducing epigenetic modifications. They also wrote the relative sections of the manuscript as well as the background and the conclusions.

The emerging role of epigenetics in human autoimmune disorders | Clinical Epigenetics | Full Text

PB contributed to the editing of the section describing chemical agents inducing sperm DNA epigenetic alterations. VG performed the search of the literature about the tools for the epigenome analysis. IA performed the search of literature about epigenetics and embryo development and wrote the relative section as well as the conclusions. All authors read and approved the final manuscript. Liborio Stuppia, Phone: 39 , Email: ti.

Marica Franzago, Email: ti. Patrizia Ballerini, Email: ti. Valentina Gatta, Email: ti. Ivana Antonucci, Email: ti. National Center for Biotechnology Information , U. Journal List Clin Epigenetics v. Clin Epigenetics. Published online Nov Author information Article notes Copyright and License information Disclaimer. Corresponding author. Received Jun 3; Accepted Nov 5. This article has been cited by other articles in PMC. Abstract The correlation between epigenetics and human reproduction represents a very interesting field of study, mainly due to the possible transgenerational effects related to epigenetic modifications of male and female gametes.

Background You shall not bow down to them or worship them; for I, the Lord your God, am a jealous God, punishing the children for the sin of the parents to the third and fourth generation of those who hate me Esodus, Molecular basis of epigenetics The main epigenetic mechanisms of gene expression regulation are represented by DNA methylation, histone modifications, and small, non-coding RNAs. Open in a separate window. Histone modifications Modifications of histone tails represent other epigenetic chromatin marks critical for transcriptional regulation.

Genomic imprinting A specific feature of epigenetic control of gene function is represented by genomic imprinting, a process leading to the expression of a specific set of genes about 70—80, the majority of which clustered in 16 specific chromosomal regions based on their maternal or paternal origin [ 59 ]. Epigenetics and spermatogenesis The process of spermatogenesis The formation of a mature sperm requires different processes, namely 1 mitotic proliferation of spermatogonia; 2 meiotic divisions; and 3 morphological differentiation of sperm precursors spermiogenesis , leading to the generation of highly specialized cells characterized by the presence of a head, an intermediate portion, and a flagellum.

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Histone—protamine replacement as the main epigenetic change in sperms In addition to the typical morphology and motility, sperms are characterized also by a highly organized chromatin structure. DNA methylation and histone modifications during spermatogenesis Various and specific epigenetic marks are required during male gametogenesis for proper maturation of gametes. Epigenetic alterations and spermatogenesis disruption The above-described epigenetic marks in germ line genes play a key role in the proper spermatogenesis processes, and several studies have demonstrated that aberrant epigenetic modification of genes expressed in the testes are associated with male infertility.

Epigenetics and embryo development DNA methylation and histone modifications play a crucial role in the process of genome reprogramming during early embryogenesis [ 87 — 89 ]. Epigenetics and ART A large amount of literature data, including human and animal studies, has raised concerns about an increased risk of different diseases in the offspring generated by the use of ART [ , ].

Data from ART in animal models Early studies carried out in mice had showed that alterations affecting the development and growth of the fetuses were linked to ovulation induction, manipulation of eggs, or embryo culture in vitro [ — ]. Data from ART in human In human, a larger prevalence of syndromes related to imprinting alteration, particularly Beckwith-Wiedemann and Angelman syndromes, has been reported in children born after ART when compared to non-ART children [ — ].

Environmental agents inducing epigenetic modifications Several environmental and lifestyle factors stress, physical activity, alcohol intake, smoke, shift work are known to affect male and female fertility [ ], and in many cases, they have been shown to influence the occurrence of epigenetic modifications with implications for human diseases [ ]. Paternal exposure to toxins or ionizing radiation Great attention has been devoted to the effects of paternal exposures to environmental toxins or low-dose ionizing radiation, and of paternal lifestyle [ ]. Paternal diet One of the most intriguing topics in the field of epigenetic modifications of the germ line is represented by the influence played by the paternal diet on gametogenesis.

The four windows of epigenetic susceptibility A crucial question concerning the role played by environmental agents in the epigenetic modifications of the male gamete is the following: when are the effects of such exposures transferred to the male gamete? Conclusions As evidenced by the large amount of studies carried out in this field, epigenetic mechanisms play a key role in the proper function of the male gamete, and alterations in these mechanisms can widely affect human reproduction. Acknowledgements This work was supported by grants form the G.

Footnotes Competing interests None of the authors has any competing interests in the manuscript. References 1. National, regional, and global trends in infertility prevalence since a systematic analysis of health surveys. PLoS Med. Krausz C. Male infertility: pathogenesis and clinical diagnosis. Male infertility: role of genetic background.

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