Epigenetics and Male Reproduction: Consequences of Paternal Lifestyle on Fertility

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Molecular basis of epigenetics
The main epigenetic mechanisms of gene expression regulation are represented by DNA methylation, histone modifications, and small, non-coding RNAs.

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 [145]. 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. demonstrated an increased risk of nervous system tumors related to paternal occupational exposure to pesticides and of leukemia related to woodwork by fathers [146]. Reid et al. evidenced the presence of high exposure to exhausts by paternal grandmothers of children with acute lymphoblastic leukemia [147]. 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 [148, 149]. Anway et al. evidenced that a transient embryonic exposure to the endocrine disruptor vinclozolin during gonadal sex determination in rats produced several diseases affecting the prostate, kidney, immune system, testis, as well as different cancers in the subsequent generations, suggesting a potential transgenerational effect [148]. Similar results were obtained by Guerrero-Bosagna et al., who showed that transient exposure of the F0 generation gestating female to vinclozolin during gonadal sex determination caused adult onset disease in the F3 generation male and female mice [149].

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. suggested an epigenetic mechanism of transmission of the radiation-exposure signal through sperm, likely involving DNA methylation and affecting DNA repair processes [150]. 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 [150].

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 [151]. 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 [152]. 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 [153]. This study highlighted an increased methylation of the differentially methylated domains (DMDs) of maternal PEG1, PEG3, and SNRPN genes and decreased methylation of paternal H19 and GTL2 genes.
Epigenetics

In recent years, great interest has been raised by the novel acquisitions on the epigenetic mechanisms of regulation of gene expression. Epigenetics can be defined as the study of mitotically or meiotically heritable modifications in the function of specific genes not related to modification in the DNA sequence [24]. This novel field of study has obtained large relevance also in the world of mass media, usually transmitting the “take-home message” that human destiny is not written inside genes, since environmental agents or experiences can influence human heredity [25]. As a matter of fact, the interaction between genes and environment in the determination of human phenotypes is very well known from many years, but the real novelties provided by the studies on epigenetics are that (1) environmental agents can modify the expression of specific genes without changing their sequence or copy number, and (2) these modifications can be transmitted to the offspring, so that either rare congenital diseases or the susceptibility to common diseases appearing during the lifetime can be the result of a gene-environment interaction that occurred in one parent of a subject, not in the subject himself. In this view, epigenetic studies represent a breakthrough in the field of human reproduction. In fact, since epigenetic modifications can be transmitted to the offspring, they obviously involve germ cells, and in some cases, they could affect gametogenesis as well as the embryo development, thus representing a potential cause of infertility of the couple. Moreover, since epigenetic alterations do not induce modification in the gene sequence or copy number, they could account for at least a portion of cases of male infertility in which no genetic abnormalities are detected using the conventional techniques of genetic analysis.

Several studies have investigated in the last years the role played by epigenetic modification in male gametogenesis and in male infertility. The aim of this review is to analyze the state-of-art of this field of research in order to give an answer to the following questions. (1) Can epigenetic mechanisms be related to the quality of the spermatogenesis process? (2) Can sperm epigenetic alterations affect embryo development? (3) Is there a relationship between sperm epigenetic modifications and outcome of assisted reproduction technique (ART) procedure? (4) Which environmental agents can be responsible for epigenetic modifications of sperm DNA?

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]. Genomic imprinting plays a key role in the regulation of resource acquisition by the offspring from the mother during prenatal and early postnatal life. Paternally and maternally imprinted genes play different roles in this mechanism, being many paternally expressed alleles able to increase resource transfer to the child, which is on the other side reduced by maternally expressed genes (“parental conflict hypothesis”) [60]. The correct balance between the activity of maternally and paternally imprinted genes can be disrupted by different mechanisms, such as chromosome deletions, uniparental disomy (UPD), or alterations in the imprinting center. In human, alterations of the process of genomic imprinting cause several congenital diseases mainly involving fetal growth (e.g., Beckwith–Wiedemann syndrome, Russell–Silver syndrome), hormone systems after birth (e.g., Albright hereditary osteodystrophy, pseudohypoparathyroidism 1A, transient neonatal diabetes mellitus), or behavior (e.g., Prader–Willi syndrome, Angelman syndrome) [60]. Moreover, imprinting alterations have been suggested as responsible for intrauterine growth restriction, in turn associated with an increased risk of cardiovascular disease, diabetes, and mental defects later in life [60, 61].

Read the complete research review by Liborio Stuppia, Marica Franzago, Patrizia Ballerini, Valentina Gatta and Ivana Antonucci here.

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