Lead (Pb) exposure can induce DNA damage and alter DNA methylation but their inter-relationships have not been adequately determined. Our overall aims were to explore such relationships and to evaluate underlying epigenetic mechanisms of Pb-induced genotoxicity in Chinese workers. Blood Pb levels (BLLs) were determined and used as individual's Pb-exposure dose and the Comet assay (i.e., % tail DNA) was conducted to evaluate DNA damage. In the screening assay, 850 K BeadChip sequencing was performed on peripheral blood from 10 controls (BLLs ≤100 μg/L) and 20 exposed workers (i.e., 10 DNA-damaged and 10 DNA-undamaged workers). Using the technique, differentially methylated positions (DMPs) between the controls and the exposed workers were identified. In addition, DMPs were identified between the DNA-undamaged and DNA-damaged workers (% tail DNA >2.14%). In our validation assay, methylation levels of four candidate genes were measured by pyrosequencing in an independent sample set (n = 305), including RRAGC (Ras related GTP binding C), USP1 (Ubiquitin specific protease 1), COPS7B (COP9 signalosome subunit 7 B) and CHEK1 (Checkpoint kinase 1). The result of comparisons between the controls and the Pb-exposed workers show that DMPs were significantly enriched in genes related to nerve conduction and cell cycle. Between DNA-damaged group and DNA-undamaged group, differentially methylated genes were enriched in the pathways related to cell cycle and DNA integrity checkpoints. Additionally, methylation levels of RRAGC and USP1 were negatively associated with BLLs (P < 0.05), and the former mediated 19.40% of the effect of Pb on the % tail DNA. These findings collectively indicated that Pb-induced DNA damage was closely related to methylation of genes in cell cycle regulation, and methylation levels of RRAGC were involved in Pb-induced genotoxicity.

The intensification of anomalous events of seawater warming and the co-occurrence with local anthropogenic stressors are threatening coastal marine habitats, including seagrasses, which form extensive underwater meadows. Eutrophication highly affects coastal environments, potentially summing up to the widespread effects of global climate changes. In the present study, we investigated for the first time in seagrasses, the transcriptional response of different plant organs (i.e., leaf and shoot apical meristem, SAM) of the Mediterranean seagrass Posidonia oceanica growing in environments with a different history of nutrient enrichment. To this end, a mesocosm experiment exposing plants to single (nutrient enrichment or temperature increase) and multiple stressors (nutrient enrichment plus temperature increase), was performed. Results revealed a differential transcriptome regulation of plants under single and multiple stressors, showing an organ-specific sensitivity depending on plants' origin. While leaf tissues were more responsive to nutrient stress, SAM revealed a higher sensitivity to temperature treatments, especially in plants already impacted in their native environment. The exposure to stress conditions induced the modulation of different biological processes. Plants living in an oligotrophic environment were more responsive to nutrients compared to plants from a eutrophic environment. Evidences that epigenetic mechanisms were involved in the regulation of transcriptional reprogramming were also observed in both plants’ organs. These results represent a further step in the comprehension of seagrass response to abiotic stressors pointing out the importance of local pressures in a global warming scenario.

Endocrine-disrupting chemicals (EDCs) are ubiquitous in daily life, but their harmful effects on the human body have not been fully explored. Recent studies have shown that EDCs exposure could lead to infertility, menstrual disorder and menopause, resulting in subsequent effects on female health. Therefore, it is of great significance to clarify and summarize the impacts of EDCs on ovarian aging for explaining the etiology of ovarian aging and maintaining female reproductive health. Here in this review, we focused on the impacts of ten typical environmental contaminants on the progression of ovarian aging during adult exposure, including epidemiological data in humans and experimental models in rodents, with their clinical phenotypes and underlying mechanisms. We found that both persistent (polychlorinated biphenyls, perfluoroalkyl and polyfluoroalkyl substances) and non-persistent (phthalates) EDCs exposure could increase an overall risk of ovarian aging, leading to the diminish of ovarian reserve, decline of fertility or fecundity, irregularity of the menstrual cycle and an earlier age at menopause, and/or premature ovarian insufficiency/failure in epidemiological studies. Among these, the loss of follicles can also be validated in experimental studies of some EDCs, such as BPA, phthalates, parabens and PCBs. The underlying mechanisms may involve the impaired ovarian follicular development by altering receptor-mediated pro-apoptotic pathways, inducing signal transduction and cell cycle arrest and epigenetic modification. However, there were inconsistent results in the impacts on fertility/fecundity, menstrual/estrous cycle and hormone changes response to different EDCs, and differences between human and animal studies. Our review summarizes the current state of knowledge on ovarian disrupters, highlights their risks to ovarian aging and identifies knowledge gaps in humans and animals. We therefore propose that females adopt healthy lifestyle changes to minimize their exposure to both persistent and non-persistent chemicals, that have the potential damage to their reproductive function.

Fine particulate matter 2.5 (PM2.5) exposure leads to the progress of pulmonary disease. It has been reported that N6-methyladenosine (m6A) modification was involved in various biological processes and diseases. However, the critical role of m6A modification in pulmonary disease during PM2.5 exposure remains elusive. Here, we revealed that lung inflammation and mucus production caused by PM2.5 were associated with m6A modification. Both in vivo and in vitro assays demonstrated that PM2.5 exposure elevated the total level of m6A modification as well as the methyltransferase like 3 (METTL3) expression. Integration analysis of m6A RNA immunoprecipitation-seq (meRIP-seq) and RNA-seq discovered that METTL3 up-regulated the expression level and the m6A modification of Interleukin 24 (IL24). Importantly, we explored that the stability of IL24 mRNA was enhanced due to the increased m6A modification. Moreover, the data from qRT-PCR showed that PM2.5 also increased YTH N6-Methyladenosine RNA Binding Protein 1 (YTHDF1) expression, and the up-regulated YTHDF1 augmented IL24 mRNA translation efficiency. Down-regulation of Mettl3 reduced Il24 expression and ameliorated the pulmonary inflammation and mucus secretion in mice exposed to PM2.5. Taken together, our finding provided a comprehensive insight for revealing the significant role of m6A regulators in the lung injury via METTL3/YTHDF1-coupled epitranscriptomal regulation of IL24.

A vast amount of evidence indicates that bisphenol A (BPA) and phthalates are widely distributed in the environment since these compounds are mass-produced for the manufacture of plastics and plasticizers. These compounds belong to a large group of substances termed endocrine-disrupting chemicals (EDC). It is well known that humans and living organisms are unavoidably and unintentionally exposed to BPA and phthalates from food packaging materials and many other everyday products. BPA and phthalates exert their effect by interfering with hormone synthesis, bioavailability, and action, thereby altering cellular proliferation and differentiation, tissue development, and the regulation of several physiological processes. In fact, these EDC can alter fetal programming at an epigenetic level, which can be transgenerational transmitted and may be involved in the development of various chronic pathologies later in the adulthood, including metabolic, reproductive and degenerative diseases, and certain types of cancer.In this review, we describe the most recent proposed mechanisms of action of these EDC and offer a compelling selection of experimental, epidemiological and clinical studies, which show evidence of how exposure to these pollutants affects our health during development, and their association with a wide range of reproductive, metabolic and neurological diseases, as well as hormone-related cancers. We stress the importance of concern in the general population and the urgent need for the medical health care system to closely monitor EDC levels in the population due to unavoidable and involuntary exposure to these pollutants and their impact on human health.

Overexpression of estrogen receptor β (ERβ) in endometrium contributes to endometriosis (EM) pathogenesis. Trimethylation of the H3 lysine (K) 4 (H3K4me3) in promoters is strongly correlated with gene expression. This study aimed to explore the effects of bisphenol A (BPA) exposure on EM development from the perspective of the regulation of ERβ expression in eutopic endometrium via the H3K4me3-related epigenetic pathway. A mouse EM model was established to investigate the effects of BPA. Immortalized human normal endometrial stromal cells (iESCs) were cultured and treated with BPA to explore the underlying mechanism. Eutopic endometria from patients with or without EM were collected and analyzed. Results showed that BPA elevated ERβ expression in mouse eutopic endometrium and promoted lesion growth. BPA also promoted WD repeat domain 5 (WDR5) expression and upregulated H3K4me3 levels in the ERβ promoter and Exon 1. Further research indicated that WDR5 interacted with tet methylcytosine dioxygenase 2 (TET2), while BPA exposure enhanced the interaction between these two proteins, promoted the recruitment of the WDR5/TET2 complex to the ERβ promoter and Exon 1, and inhibited DNA methylation of CpG islands. The WDR5/TET2 interaction was essential for BPA-induced ERβ overexpression. Enhanced WDR5/TET2 interaction was also observed in eutopic endometria from EM patients. Further results showed that BPA upregulated WDR5 expression through the G protein-coupled estrogen receptor (GPER)-mediated PI3K/mTOR signaling pathway. In conclusion, our study suggests that BPA exposure promotes EM development by upregulating ERβ expression in eutopic endometrium via the WDR5/TET2-mediated epigenetic pathway.

Exposure to environmental endocrine disrupting chemicals (EDCs) is highly suspected in prostate carcinogenesis. Though, estrogenicity is the most studied behavior of EDCs, the androgenic potential of most of the EDCs remains elusive. This study investigates the androgen mimicking potential of some common EDCs and their effect in androgen-dependent prostate cancer (LNCaP) cells. Based on the In silico interaction study, all the 8 EDCs tested were found to interact with androgen receptor with different binding energies. Further, the luciferase reporter activity confirmed the androgen mimicking potential of 4 EDCs namely benzo[a]pyrene, dichlorvos, genistein and β-endosulfan. Whereas, aldrin, malathion, tebuconazole and DDT were reported as antiandrogenic in luciferase reporter activity assay. Next, the nanomolar concentration of androgen mimicking EDCs (benzo[a]pyrene, dichlorvos, genistein and β-endosulfan) significantly enhanced the expression of AR protein and subsequent nuclear translocation in LNCaP cells. Our In silico studies further demonstrated that androgenic EDCs also bind with epigenetic regulatory enzymes namely DNMT1 and HDAC1. Moreover, exposure to these EDCs enhanced the protein expression of DNMT1 and HDAC1 in LNCaP cells. These observations suggest that EDCs may regulate proliferation in androgen sensitive LNCaP cells by acting as androgen mimicking ligands for AR signaling as well as by regulating epigenetic machinery. Both androgenic potential and epigenetic modulatory effects of EDCs may underlie the development and growth of prostate cancer.

The methylcytosine dioxygenase Ten-eleven translocation 1 (TET1) is an important regulator for the balance of DNA methylation and hydroxymethylation through various pathways. Increasing evidence has suggested that TET1 probably involved in DNA methylation and demethylation dysregulation during chemical carcinogenesis. However, the role and mechanism of TET1 during lung cancer remains unclear. In this study, we found that TET1 expression was significantly down-regulated and the methylation level was significantly up-regulated in 3-methylcholanthrene (3-MCA) induced cell malignant transformation model, rat chemical carcinogenesis model, and human lung cancer tissues. Demethylation experiment further confirmed that DNA methylation negatively regulated TET1 gene expression. TET1 overexpression inhibited cell proliferation, migration and invasion in vitro and in vivo, while knockdown of TET1 resulted in an opposite phenotype. DNA hydroxymethylation level in the promoter region of base excision repair (BER) pathway key genes XRCC1, OGG1, APEX1 significantly decreased and the degree of methylation gradually increased in malignant transformed cells. After differential expression of TET1, the level of hydroxymethylation, methylation and expression of these genes also changed significantly. Furthermore, TET1 binds to XRCC1, OGG1, and APEX1 to maintain them hydroxymethylated. Blockade of BER pathway key gene alone or in combination significantly diminished the effect of TET1. Our study demonstrated for the first time that TET1 expression is regulated by DNA methylation and TET1-mediated hydroxymethylation regulates BER pathway to inhibit the proliferation, migration and invasion during 3-MCA-induced lung carcinogenesis. These results suggested that TET1 gene can be a potential biomarker and therapy target for lung cancer.

Heart development requires a precise temporal regulation of gene expression in cardiomyoblasts. Therefore, the transcriptional changes in differentiating cells can lead to congenital heart diseases. Although the genetic mutations underlie most of these alterations, exposure to environmental contaminants, such as bisphenol A (BPA), has been recently considered as a risk factor as well. In this study we investigated the genotoxic and epigenotoxic effects of BPA throughout cardiomyocyte differentiation. H9c2 cells (rat myoblasts) were exposed to 10 and 30 μM BPA before and during the last two days of cardiac-driven differentiation. Then, we have analysed the phenotypic and molecular modifications (at transcriptional, genetic and epigenetic level). The results showed that treated myoblasts developed a skeletal muscle cell-like phenotype. The transcriptional changes induced by BPA in genes codifying proteins involved in heart differentiation and function depend on the window of exposure to BPA. The exposure before differentiation repressed the expression of heart transcription factors (Hand2 and Gata4), whereas exposure during differentiation reduced the expression of cardiac-specific genes (Tnnt2, Myom2, Sln, and Atp2a1). Additionally, significant effects were observed regarding DNA damage and histone acetylation levels after the two periods of BPA exposure: in cells exposed to the toxicant the percentage of DNA repair foci (formed by the co-localization of γH2AX and 53BP1) increased in a dose-dependent manner, whereas the treatment with the toxicant triggered a decrease in the epigenetic marks H3K9ac and H3K27ac. Our in vitro results reveal that BPA seriously interferes with the process of cardiomyocyte differentiation, which could be related to the reported in vivo effects of this toxicant on cardiogenesis.

MicroRNAs (miRNAs) are a class of small, non-coding RNAs with a post-transcriptional regulatory function on gene expression and cell processes, including proliferation, apoptosis and differentiation. In recent decades, miRNAs have attracted increasing interest to explore the role of epigenetics in response to air pollution. Air pollution, which always contains kinds of particulate matters, are able to reach respiratory tract and blood circulation and then causing epigenetics changes. In addition, extensive studies have illustrated that miRNAs serve as a bridge between particulate matter exposure and health-related effects, like inflammatory cytokines, blood pressure, vascular condition and lung function. The purpose of this review is to summarize the present knowledge about the expression of miRNAs in response to particulate matter exposure. Epidemiological and experimental studies were reviewed in two parts according to the size and source of particles. In this review, we also discussed various functions of the altered miRNAs and predicted potential biological mechanism participated in particulate matter-induced health effects. More rigorous studies are worth conducting to understand contribution of particulate matter on miRNAs alteration and the etiology between environmental exposure and disease development.