Epigenetic Inheritance Research Articles

Mutator Foci Are Regulated by Developmental Stage, RNA, and the Germline Cell Cycle in Caenorhabditis elegans.

RNA interference is a crucial gene regulatory mechanism in Caenorhabditis elegans. Phase-separated perinuclear germline compartments called Mutator foci are a key element of RNAi, ensuring robust gene silencing and transgenerational epigenetic inheritance. Despite their importance, Mutator foci regulation is not well understood, and observations of Mutator foci have been largely limited to adult hermaphrodite germlines. Here we reveal that punctate Mutator foci arise in the progenitor germ cells of early embryos and persist throughout all larval stages. They are additionally present throughout the male germline and in the cytoplasm of post-meiotic spermatids, suggestive of a role in paternal epigenetic inheritance. In the adult germline, transcriptional inhibition results in a pachytene-specific loss of Mutator foci, indicating that Mutator foci are partially reliant on RNA for their stability. Finally, we demonstrate that Mutator foci intensity is modulated by the stage of the germline cell cycle and specifically, that Mutator foci are brightest and most robust in the mitotic cells, transition zone, and late pachytene of adult germlines. Thus, our data defines several new factors that modulate Mutator foci morphology which may ultimately have implications for efficacy of RNAi in certain cell stages or environments.

I6mA-stack: A stacking ensemble-based computational prediction of DNA N6-methyladenine (6mA) sites in the Rosaceae genome

DNA N6-methyladenine (6 mA) is an epigenetic modification that plays a vital role in a variety of cellular processes in both eukaryotes and prokaryotes. Accurate information of 6 mA sites in the Rosaceae genome may assist in understanding genomic 6 mA distributions and various biological functions such as epigenetic inheritance. Various studies have shown the possibility of identifying 6 mA sites through experiments, but the procedures are time-consuming and costly. To overcome the drawbacks of experimental methods, we propose an accurate computational paradigm based on a machine learning (ML) technique to identify 6 mA sites in Rosa chinensis (R.chinensis) and Fragaria vesca (F.vesca). To improve the performance of the proposed model and to avoid overfitting, a recursive feature elimination with cross-validation (RFECV) strategy is used to extract the optimal number of features (ONF) subset from five different DNA sequence encoding schemes, i.e., Binary Encoding (BE), Ring-Function-Hydrogen-Chemical Properties (RFHC), Electron-Ion-Interaction Pseudo Potentials of Nucleotides (EIIP), Dinucleotide Physicochemical Properties (DPCP), and Trinucleotide Physicochemical Properties (TPCP). Subsequently, we use the ONF subset to train a double layers of ML-based stacking model to create a bioinformatics tool named ‘i6mA-stack’. This tool outperforms its peer tool in general and is currently available at http://nsclbio.jbnu.ac.kr/tools/i6mA-stack/

Epigenetic Mechanisms Contribute to Evolutionary Adaptation of Gene Network Activity under Environmental Selection

SUMMARYHow evolution can be facilitated by epigenetic mechanisms has received refreshed attention recently. To explore the role epigenetic inheritance plays in evolution, we subject isogenic wild-type yeast cells expressing PGAL1-YFP (yellow fluorescent protein) to selection by daily sorting based on reporter expression. We observe expression-level reductions in multiple replicates sorted for the lowest expression that persist for several days, even after lifting the selection pressure. Reduced expression is due to factors in the galactose (GAL) network rather than global factors. Results using a constitutively active GAL network are in overall agreement with findings with the wild-type network. We find that the local chromatin environment of the reporter has a significant effect on the observed phenotype. Genome sequencing, chromatin immunoprecipitation (ChIP)-qPCR, and sporulation analysis provide further insights into the epigenetic and genetic contributors to the expression changes observed. Our work provides a comprehensive example of the role played by epigenetic mechanisms on gene network evolution.

Limitations to intergenerational inheritance: subchronic paternal stress preconception does not influence offspring anxiety

Independent studies have observed that a paternal history of stress or trauma is associated with his children having a greater likelihood of developing psychopathologies such as anxiety disorders. This father-to-child effect is reproduced in several mouse models of stress, which have been crucial in developing a greater understanding of intergenerational epigenetic inheritance. We previously reported that treatment of C57Bl/6J male breeders with low-dose corticosterone (CORT) for 28 days prior to mating yielded increased anxiety-related behaviours in their male F1 offspring. The present study aimed to determine whether subchronic 7-day CORT treatment of male mice just prior to mating would be sufficient to induce intergenerational modifications of anxiety-related behaviours in offspring. We report that subchronic CORT treatment of male breeders reduced their week-on-week body weight gain and altered NR3C1 and CRH gene expression in the hypothalamus. There were no effects on sperm count and glucocorticoid receptor protein levels within the epididymal tissue of male breeders. Regarding the F1 offspring, screening for anxiety-related behaviours using the elevated-plus maze, light–dark box, and novelty-suppressed feeding test revealed no differences between the offspring of CORT-treated breeders compared to controls. Thus, it is crucial that future studies take into consideration the duration of exposure when assessing the intergenerational impacts of paternal health.

The social construction of the social epigenome and the larger biological context

Epigenetics researchers in developmental, cell, and molecular biology greatly diverge in their understanding and definitions of epigenetics. In contrast, social epigeneticists, e.g., sociologists, scholars of STS, and behavioural scientists, share a focus and definition of epigenetics that is environmentally caused and trans-generationally inherited. This article demonstrates that this emphasis on the environment and on so-called Lamarckian inheritance, in addition to other factors, reflects an interdisciplinary power struggle with genetics, in which epigenetics appears to grant the social sciences a higher epistemic status. Social scientists’ understanding of epigenetics, thus, appears in part to be socially constructed, i.e., the result of extra-scientific factors, such as social processes and the self-interest of the discipline. This article argues that social epigeneticists make far-reaching claims by selecting elements from research labelled epigenetics in biology while ignoring widely confirmed scientific facts in genetics and cell biology, such as the dependence of epigenetic marks on DNA sequence-specific events, or the lack of evidence for the lasting influence of the environment on epigenetic marks or the epigenome. Moreover, they treat as a given crucial questions that are far from resolved, such as what role, if any, DNA methylation plays in the complex biochemical system of regulating gene activity. The article also points out incorrect perceptions and media hypes among biological epigeneticists and calls attention to an apparent bias among scientific journals that prefer papers that promote transgenerational epigenetic inheritance over articles that critique it. The article concludes that while research labelled epigenetics contributes significantly to our knowledge about chromatin and the genome, it does not, as is often claimed, rehabilitate Lamarck or overthrow the fundamental biological principles of gene regulation, which are based on specific regulatory sequences of the genome.

Single-molecule imaging reveals control of parental histone recycling by free histones during DNA replication.

During replication, nucleosomes are disrupted ahead of the replication fork, followed by their reassembly on daughter strands from the pool of recycled parental and new histones. However, because no previous studies have managed to capture the moment that replication forks encounter nucleosomes, the mechanism of recycling has remained unclear. Here, through real-time single-molecule visualization of replication fork progression in Xenopus egg extracts, we determine explicitly the outcome of fork collisions with nucleosomes. Most of the parental histones are evicted from the DNA, with histone recycling, nucleosome sliding, and replication fork stalling also occurring but at lower frequencies. Critically, we find that local histone recycling becomes dominant upon depletion of endogenous histones from extracts, revealing that free histone concentration is a key modulator of parental histone dynamics at the replication fork. The mechanistic details revealed by these studies have major implications for our understanding of epigenetic inheritance.

Stable inheritance of CENP-A chromatin: Inner strength versus dynamic control.

Chromosome segregation during cell division is driven by mitotic spindle attachment to the centromere region on each chromosome. Centromeres form a protein scaffold defined by chromatin featuring CENP-A, a conserved histone H3 variant, in a manner largely independent of local DNA cis elements. CENP-A nucleosomes fulfill two essential criteria to epigenetically identify the centromere. They undergo self-templated duplication to reestablish centromeric chromatin following DNA replication. More importantly, CENP-A incorporated into centromeric chromatin is stably transmitted through consecutive cell division cycles. CENP-A nucleosomes have unique structural properties and binding partners that potentially explain their long lifetime in vivo. However, rather than a static building block, centromeric chromatin is dynamically regulated throughout the cell cycle, indicating that CENP-A stability is also controlled by external factors. We discuss recent insights and identify the outstanding questions on how dynamic control of the long-term stability of CENP-A ensures epigenetic centromere inheritance.

Epigenome-wide association study for transgenerational disease sperm epimutation biomarkers following ancestral exposure to jet fuel hydrocarbons

Jet fuel hydrocarbons is the generic name for aviation fuels used in gas-turbine engine powered aircraft. The Deepwater Horizon oil rig explosion created the largest environmental disaster in U.S. history, and the second largest oil spill in human history with over 800 million liters of hydrocarbons released into the Gulf of Mexico over a period of 3 months. Due to the widespread use of jet fuel hydrocarbons, this compound mixture has been recognized as the single largest chemical exposure for military personnel. Previous animal studies have demonstrated the ability of jet fuel (JP-8) exposure to promote the epigenetic transgenerational inheritance of disease susceptibility in subsequent generations. The diseases observed include late puberty, kidney, obesity and multiple disease pathologies. The current study is distinct and was designed to identify potential sperm DNA methylation biomarkers for specific transgenerational diseases. Observations show disease specific differential DNA methylation regions (DMRs) called epimutations in the transgenerational F3 generation great-grand-offspring male rats ancestrally exposed to jet fuel. The potential epigenetic DMR biomarkers were identified for late puberty, kidney, obesity, and multiple diseases, and found to be predominantly disease specific. These disease specific DMRs have associated genes that were previously shown to be linked with each of these specific diseases. Therefore, the germline (i.e. sperm) has environmentally induced ancestrally derived epimutations that have the potential to transgenerationally transmit disease susceptibilities to subsequent generations. Epigenetic biomarkers for specific diseases could be developed as medical diagnostics to facilitate clinical management of disease, and allow preventative medicine therapeutics.

An environmentally relevant mixture of polychlorinated biphenyls (PCBs) and polybrominated diphenylethers (PBDEs) disrupts mitochondrial function, lipid metabolism and neurotransmission in the brain of exposed zebrafish and their unexposed F2 offspring

Polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) are persistent organic pollutants still present in aquatic environments despite their total or partial ban. Previously, we observed that an environmentally realistic mixture of these compounds affects energy balance, growth, and reproduction in exposed zebrafish (F0), and behavior in their unexposed offspring (F1-F4). In the present work, we performed lipidomic and transcriptomic analyses on brains of zebrafish (F0-F2) from exposed and control lineages to identify molecular changes that could explain the observed phenotypes. The use of both technologies highlighted that F0 zebrafish displayed impaired mitochondrial function and lipid metabolism regulation (depletion in triacylglycerols and phospholipids) which can explain disruption of energy homeostasis. A subset of the regulated biological pathways related to energetic metabolism and neurotransmission were inherited in F2. In addition, there were increasing effects on epigenetic pathways from the F0 to the F2 generation. Altogether, we show that the effects of an environmental exposure to PCBs and PBDEs on energetic metabolism as well as neurotransmission extend over 2 generations of zebrafish, possibly due to transgenerational epigenetic inheritance.

N-Terminus Does Not Govern Protein Turnover of Schizosaccharomyces pombe CENP-A.

Centromere integrity underlies an essential framework for precise chromosome segregation and epigenetic inheritance. Although centromeric DNA sequences vary among different organisms, all eukaryotic centromeres comprise a centromere-specific histone H3 variant, centromeric protein A (CENP-A), on which other centromeric proteins assemble into the kinetochore complex. This complex connects chromosomes to mitotic spindle microtubules to ensure accurate partitioning of the genome into daughter cells. Overexpression of CENP-A is associated with many cancers and is correlated with its mistargeting, forming extra-centromeric kinetochore structures. The mislocalization of CENP-A can be counteracted by proteolysis. The amino (N)-terminal domain (NTD) of CENP-A has been implicated in this regulation and shown to be dependent on the proline residues within this domain in Saccharomyces cerevisiae CENP-A, Cse4. We recently identified a proline-rich GRANT motif in the NTD of Schizosaccharomyces pombe CENP-A (SpCENP-A) that regulates the centromeric targeting of CENP-A via binding to the CENP-A chaperone Sim3. Here, we investigated whether the NTD is required to confer SpCENP-A turnover (i.e., counter stability) using various truncation mutants of SpCENP-A. We show that sequential truncation of the NTD did not improve the stability of the protein, indicating that the NTD of SpCENP-A does not drive turnover of the protein. Instead, we reproduced previous observations that heterochromatin integrity is important for SpCENP-A stability, and showed that this occurs in an NTD-independent manner. Cells bearing the null mutant of the histone H3 lysine 9 methyltransferase Clr4 (Δclr4), which have compromised constitutive heterochromatin integrity, showed reductions in the proportion of SpCENP-A in the chromatin-containing insoluble fraction of the cell extract, suggesting that heterochromatin may promote SpCENP-A chromatin incorporation. Thus, a disruption in heterochromatin may result in the delocalization of SpCENP-A from chromatin, thus exposing it to protein turnover. Taken together, we show that the NTD is not required to confer SpCENP-A protein turnover.

Small RNA modifications in Alzheimer's disease

BackgroundWhile significant advances have been made in uncovering the aetiology of Alzheimer's disease and related dementias at the genetic level, molecular events at the epigenetic level remain largely undefined. Emerging evidence indicates that small non-coding RNAs (sncRNAs) and their associated RNA modifications are important regulators of complex physiological and pathological processes, including aging, stress responses, and epigenetic inheritance. However, whether small RNAs and their modifications are altered in dementia is not known.MethodsWe performed LC-MS/MS–based, high-throughput assays of small RNA modifications in post-mortem samples of the prefrontal lobe cortices of Alzheimer's disease (AD) and control individuals. We noted that some of the AD patients has co-occurring vascular cognitive impairment-related pathology (VaD).FindingsWe report altered small RNA modifications in AD samples compared with normal controls. The 15–25-nucleotide (nt) RNA fraction of these samples was enriched for microRNAs, whereas the 30–40-nt RNA fraction was enriched for tRNA-derived small RNAs (tsRNAs), rRNA-derived small RNAs (rsRNAs), and YRNA-derived small RNAs (ysRNAs). Interestingly, most of these altered RNA modifications were detected both in the AD and AD with co-occurring vascular dementia subjects. In addition, sequencing of small RNA in the 30–40-nt fraction from AD cortices revealed reductions in rsRNA-5S, tsRNA-Tyr, and tsRNA-Arg.InterpretationThese data suggest that sncRNAs and their associated modifications are novel signals that may be linked to the pathogenesis and development of Alzheimer's disease.FundNIH grants (R01HL122770, R01HL091905, 1P20GM130459, R01HD092431, P50HD098593, GM103440), AHA grant (17IRG33370128), Sigmund Gestetner Foundation Fellowship to P Kehoe.

Caenorhabditis elegans nuclear RNAi factor SET-32 deposits the transgenerational histone modification, H3K23me3.

Nuclear RNAi provides a highly tractable system to study RNA-mediated chromatin changes and epigenetic inheritance. Recent studies have indicated that the regulation and function of nuclear RNAi-mediated heterochromatin are highly complex. Our knowledge of histone modifications and the corresponding histonemodifying enzymes involved in the system remains limited. In this study, we show that the heterochromatin mark, H3K23me3, is induced by nuclear RNAi at both exogenous and endogenous targets in C. elegans. In addition, dsRNA-induced H3K23me3 can persist for multiple generations after the dsRNA exposure has stopped. We demonstrate that the histone methyltransferase SET-32, methylates H3K23 in vitro. Both set-32 and the germline nuclear RNAi Argonaute, hrde-1, are required for nuclear RNAi-induced H3K23me3 in vivo. Our data poise H3K23me3 as an additional chromatin modification in the nuclear RNAi pathway and provides the field with a new target for uncovering the role of heterochromatin in transgenerational epigenetic silencing.

Environmental Impact on Male (In)Fertility via Epigenetic Route.

In the last 40 years, male reproductive health—which is very sensitive to both environmental exposure and metabolic status—has deteriorated and the poor sperm quality observed has been suggested to affect offspring development and its health in adult life. In this scenario, evidence now suggests that epigenetics shapes endocrine functions, linking genetics and environment. During fertilization, spermatozoa share with the oocyte their epigenome, along with their haploid genome, in order to orchestrate embryo development. The epigenetic signature of spermatozoa is the result of a dynamic modulation of the epigenetic marks occurring, firstly, in the testis—during germ cell progression—then, along the epididymis, where spermatozoa still receive molecules, conveyed by epididymosomes. Paternal lifestyle, including nutrition and exposure to hazardous substances, alters the phenotype of the next generations, through the remodeling of a sperm epigenetic blueprint that dynamically reacts to a wide range of environmental and lifestyle stressors. With that in mind, this review will summarize and discuss insights into germline epigenetic plasticity caused by environmental stimuli and diet and how spermatozoa may be carriers of induced epimutations across generations through a mechanism known as paternal transgenerational epigenetic inheritance.

Strain-Specific Epigenetic Regulation of Endogenous Retroviruses: The Role of Trans-Acting Modifiers.

Approximately 10 percent of the mouse genome consists of endogenous retroviruses (ERVs), relics of ancient retroviral infections that are classified based on their relatedness to exogenous retroviral genera. Because of the ability of ERVs to retrotranspose, as well as their cis-acting regulatory potential due to functional elements located within the elements, mammalian ERVs are generally subject to epigenetic silencing by DNA methylation and repressive histone modifications. The mobilisation and expansion of ERV elements is strain-specific, leading to ERVs being highly polymorphic between inbred mouse strains, hinting at the possibility of the strain-specific regulation of ERVs. In this review, we describe the existing evidence of mouse strain-specific epigenetic control of ERVs and discuss the implications of differential ERV regulation on epigenetic inheritance models. We consider Krüppel-associated box domain (KRAB) zinc finger proteins as likely candidates for strain-specific ERV modifiers, drawing on insights gained from the study of the strain-specific behaviour of transgenes. We conclude by considering the coevolution of KRAB zinc finger proteins and actively transposing ERV elements, and highlight the importance of cross-strain studies in elucidating the mechanisms and consequences of strain-specific ERV regulation.

Cytological and yield-related analyses in offspring of primed bread wheat (Triticum aestivum L.) seeds

Seed priming with distilled water (hydropriming) and with micronutrients (nutripriming) can improve the agronomic performance of various crops. Iron (Fe) and Zinc (Zn) are essential micronutrients for plants and humans that have been widely used in wheat biofortification. However, the micronutrients excess can generate cyto- and phytotoxicity affecting the germination, cell division, development and yield. Seed priming is repeated in each generation, and its effects were never studied in the offspring of primed plants. Whether its advantages, cyto- or phytotoxicity are transmitted to the unprimed offspring are unknown. In this work, we used the first generation of seeds (S1) harvested in plants whose seeds (S0) were hydroprimed and nutriprimed with 4 mg L−1 and/or 8 mg L−1 of Fe and/or Zn. We aimed to study their germination, mitotic cell cycle and seven yield-related components in the adult plants, for further comparison with the data achieved in the S0 generation. A germination percentage of 100% was verified in all S1 offspring. Despite the higher values of the percentage of dividing cells with anomalies (%DCA) in S1 relative to S0, a lower number of types of mitotic irregularities, was found, suggesting cytotoxicity attenuation. The S1 surpassed the S0 for all the yield-related components. Our results suggested that the beneficial effects of hydropriming and Fe and/or Zn nutripriming performed in S0 seeds were enhanced in the S1 offspring via seed provisioning and by the epigenetic inheritance of DNA hypomethylation patterns previously detected in the S0 generation.

Imprecise DNMT1 activity coupled with neighbor-guided correction enables robust yet flexible epigenetic inheritance.

The epigenome, including DNA methylation, is stably propagated during mitotic division. However, single-cell clonal expansion produces heterogeneous methylomes, thus raising the question of how the DNA methylome remains stable despite constant epigenetic drift. Here, we report that a clonal population of DNA (cytosine-5)-methyltransferase 1 (DNMT1)-only cells produces a heterogeneous methylome, which is robustly propagated on cell expansion and differentiation. Our data show that DNMT1 has imprecise maintenance activity and possibly possesses weak de novo activity, leading to spontaneous 'epimutations'. However, these epimutations tend to be corrected through a neighbor-guided mechanism, which is likely to be enabled by the environment-sensitive de novo activity ('tuner') and maintenance activity ('stabilizer') of DNMT1. By generating base-resolution maps of de novo and maintenance activities, we find that H3K9me2/3-marked regions show enhanced de novo activity, and CpG islands have both poor maintenance and de novo activities. The imprecise epigenetic machinery coupled with neighbor-guided correction may be a fundamental mechanism underlying robust yet flexible epigenetic inheritance.

Nutri-Epigenetics and Gut Microbiota: How Birth Care, Bonding and Breastfeeding Can Influence and Be Influenced?

Maternal lifestyle is an important factor in the programming of an infant’s epigenome, in particular when considered alongside the mode of birth and choice of feeding method (i.e., breastfeeding or formula feeding). Beginning in utero, and during the first two years of an infant’s life, cells acquire an epigenetic memory of the neonatal exposome which can be influential across the entire lifespan. Parental lifestyle (e.g., malnutrition, alcohol intake, smoke, stress, exposure to xenobiotics and/or drugs) can modify both the maternal and paternal epigenome, leading to epigenetic inheritance in their offspring. This review aims to outline the origin of early life modulation of the epigenome, and to share this fundamental concept with all the health care professionals involved in the development and provision of care during childbirth in order to inform future parents and clinicians of the importance of the this process and the key role it plays in the programming of a child’s health.

Diet and Transgenerational Epigenetic Inheritance of Breast Cancer: The Role of the Paternal Germline.

The past decade has made evident that in addition to passing their genetic material at conception, parents also transmit a molecular memory of past environmental experiences, including nutritional status, to their progeny through epigenetic mechanisms. In the 1990s, it was proposed that breast cancer originates in utero. Since then, an overwhelming number of studies in human cohorts and animal models have provided support for that hypothesis. It is becoming clear, however, that exposure in the parent generation can lead to multigenerational and transgenerational inheritance of breast cancer. Importantly, recent data from our lab and others show that pre-conception paternal diets reprogram the male germline and modulate breast cancer development in offspring. This review explores the emerging evidence for transgenerational epigenetic inheritance of breast cancer focusing on studies associated with ancestral nutritional factors or related markers such as birth weight. We also explore paternal factors and the epigenetic mechanisms of inheritance through the male germline while also reviewing the existing literature on maternal exposures in pregnancy and its effects on subsequent generations. Finally, we discuss the importance of this mode of inheritance in the context of breast cancer prevention, the challenges, and outstanding research questions in the field.

Developmental origins of transgenerational sperm histone retention following ancestral exposures

Numerous environmental toxicants have been shown to induce the epigenetic transgenerational inheritance of disease and phenotypic variation. Alterations in the germline epigenome are necessary to transmit transgenerational phenotypes. In previous studies, the pesticide DDT (dichlorodiphenyltrichloroethane) and the agricultural fungicide vinclozolin were shown to promote the transgenerational inheritance of sperm differential DNA methylation regions, non-coding RNAs and histone retention, which are termed epimutations. These epimutations are able to mediate this epigenetic inheritance of disease and phenotypic variation. The current study was designed to investigate the developmental origins of the transgenerational differential histone retention sites (called DHRs) during gametogenesis of the sperm. Vinclozolin and DDT were independently used to promote the epigenetic transgenerational inheritance of these DHRs. Male control lineage, DDT lineage and vinclozolin lineage F3 generation rats were used to isolate round spermatids, caput epididymal spermatozoa, and caudal sperm. The DHRs distinguishing the control versus DDT lineage or vinclozolin lineage samples were determined at these three developmental stages. DHRs and a reproducible core of histone H3 retention sites were observed using an H3 chromatin immunoprecipitation-sequencing (ChIP-Seq) analysis in each of the germ cell populations. The chromosomal locations and genomic features of the DHRs were analyzed. A cascade of epigenetic histone retention site alterations was found to be initiated in the round spermatids and then further modified during epididymal sperm maturation. Observations show that in addition to alterations in sperm DNA methylation and ncRNA expression previously identified, the induction of differential histone retention sites (DHRs) in the later stages of spermatogenesis also occurs. This novel component of epigenetic programming during spermatogenesis can be environmentally altered and transmitted to subsequent generations through epigenetic transgenerational inheritance.

Current mechanistic perspectives on male reproductive toxicity induced by heavy metals

Environmental and occupational exposures to heavy metals have led to various deleterious damages to the biological system of which infertility is one of them. Infertility is a global public health concern, affecting 15% of all couples of reproductive age. Out of the 100% cases of reported infertility among couples, 40% of the cases are related to male factors; including decreased semen quality. This review focuses on the recent mechanistic perspectives of heavy metal-induced male reproductive toxicity. The associated toxic metal-mediated mechanisms of male reproductive toxicity include ion mimicry, disruption of cell signaling pathways, oxidative stress, altered gene expression, epigenetic regulation of gene expression, apoptosis, disruption of testis/blood barrier, inflammation and endocrine disruption. The current literature suggests that non-coding RNAs (ncRNAs) mediate paternal intergenerational epigenetic inheritance and thus has a direct functional importance, as well as possess novel biomarker potential, for male reproductive toxicity. To identify the specific ncRNAs with the most profound impacts on heavy metal-induced male reproductive toxicity should be thrust of further research.