Search

Cadmium (Cd) and its compounds are well-known human carcinogens, but the mechanisms underlying the carcinogenesis are not well understood. This study aimed to investigate whether long noncoding RNA (LncRNA)–ENST00000446135 could serve as a novel biomarker of Cd toxicity in cells, animals, and Cd-exposed workers and regulate DNA damage and repair. LncRNA–ENST00000446135 expression increased gradually in cadmium chloride-transformed 16HBE cells. Small interfering RNA-mediated knockdown of LncRNA–ENST00000446135 inhibited the growth of DNA-damaged cells and decreased the expressions of DNA damage-related genes (ATM, ATR, and ATRIP), whereas increased the expressions of DNA repair-related genes (DDB1, DDB2, OGG1, ERCC1, MSH2, XRCC1, and BARD1). Chromatin immunoprecipitation-sequencing showed that MSH2 is a direct transcriptional target of lncRNA–ENST00000446135. Cadmium increased lncRNA–ENST00000446135 expression in the lung of Cd-exposed rats in a dose-dependent manner. A significant positive correlation was observed between blood ENST00000446135 expression and urinary/blood Cd concentrations, and there were significant correlations of LncRNA–ENST00000446135 expression with the DNA damage cell and the expressions of target genes in the lung of Cd-exposed rats and the blood of Cd-exposed workers and significantly correlated with liver and renal function in Cd-exposed workers. These results indicate that the expression of LncRNA–ENST00000446135 is upregulated and may serve as a signature for DNA damage and repair related to the epigenetic mechanisms underlying the cadmium toxicity and become a novel biomarker of cadmium toxicity.

In our previous study, we found that subchronic exposure of chlorpyrifos (CPF) can cause reproductive damage in male rats. However, the mechanisms underlying the reproductive effects of CPF are not well understood. DNA methylation is essential for epigenetic gene regulation in development and disease. Therefore, we aim to compare DNA methylation profiles between controls and CPF-treated rats in order to identify the epigenetic mechanism of male reproductive toxicity induced by CPF. Methylated DNA immunoprecipitation with high-throughput sequencing (MeDIP-seq) was used to investigate the genome-wide DNA methylation pattern in testes of control and CPF-treated rats for 90 days. We identified 27 019 differentially methylated regions (DMRs) (14 150 upmethylated and 12 869 downmethylated) between CPF-exposed and control groups. The DMR-related genes are mainly involved in 113 pathways predicted by Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The result showed that high methylation gene PIK3CD may play a key role in epigenetic regulation of multiple pathways, such as Ras signaling pathway, AGE–RAGE signaling pathway in diabetic complications, HIF-1 signaling pathway, VEGF signaling pathway, and glioma and Fc epsilon RI signaling pathway in rats exposed to CPF. Our study provides significant explanations for the epigenetic mechanism of male reproductive toxicology induced by CPF.

Growing evidence indicates that arsenic can cause long-lasting and irreversible damage to the function of the human immune system. It is known that forkhead box protein 3(Foxp3), which is specifically expressed in regulatory T cells (Tregs), plays a decisive role in immunoregulation and is regulated by DNA methylation. While evidence suggests that epigenetic regulated Foxp3 is involved in the immune disorders caused by arsenic exposure, the specific mechanism remains unclear. In this study, after primary human lymphocytes were treated with different doses of NaAsO2, our results showed that arsenic induced the high expression of DNMT1 and Foxp3 gene promoter methylation level, thereby inhibiting the expression levels of Foxp3, followed by decreasing Tregs and reducing related anti-inflammatory cytokines, such as interleukin 10 (IL-10) and interleukin 10 (IL-35), and increasing the ratio of CD4+/CD8+ T cells in lymphocytes. Treatment with DNA methyltransferase inhibitor 5-Aza-CdR can notably inhibit the expression of DNMT1, effectively restoring the hypermethylation of the Foxp3 promoter region in primary human lymphocytes and upregulating the expression levels of Foxp3, balancing the ratio of CD4+/CD8+ T cells in lymphocytes. It also activates the secretion of anti-inflammatory cytokines and restores the immune regulatory functions of Tregs. In conclusion, our study provides limited evidence that DNMT1-mediated Foxp3 gene promoter hypermethylation is involved in immune dysfunction caused by arsenic in primary human lymphocytes. The study can provide a scientific basis for further understanding the arsenic-induced immune dysfunction in primary human lymphocytes.

Sirtuin 1 (SIRT1), the NAD-dependent histone deacetylase, has been extensively investigated due to its cognitive protective effect. Studies suggest microRNAs (miRNAs) and histone modifications are key epigenetic regulators of gene expression and play important role in brain development. We previously showed that cognitive impairment by lead (Pb) was associated with downregulation of SIRT1, but the epigenetic role of this is unclear. Thus, we exposed 4-week-old male mice to 0.2% lead acetate solution for three months, and subsequently extracted brain homogenate from mice cortex and hippocampus at the age of 1, 4, and 16 months, respectively. In this study, we found that the protein level of SIRT1 was inhibited in the hippocampus and cortex of 16-month-old aged mice exposed to Pb. Moreover, changes in the levels of miR-138-5p and miR-141-3p, which were considered to the mechanistic target of SIRT1 by bioinformatic analysis, were negative correlations SIRT1 protein expression. We also found miR-34c-3p expression was increased in the cortex of mice at the age of 16 months. Collectively, our results showed the expression of neural SIRT1 and three selected microRNAs at different age nodes of mice for the first time of following Pb exposure. Our results suggest that additional efforts should focus on the consequences of early Pb exposure from an epigenetic perspective.

Although moderate homocysteine (HCY) elevation is associated with neural tube defects (NTDs), the underlying mechanisms have not been elucidated. In this study, we aimed to investigate that whether HCY-induced NTDs were associated with oxidative stress and methyl metabolism in chick embryos. The potential role of miR-124 in neurogenesis was also investigated. In this study, increased intracellular oxidative species and alterations in DNA methylation were observed following HCY treatment. This alteration coincided with decreases of Mn superoxide dismutase and glutathione peroxidase activities, as well as the expression of anti-rabbit DNA methyltransferase (DNMT) 1 and 3a. In addition, HCY induced significant decreases of S-adenosylmethionine (SAM)/S-adenosylhomocysteine (SAH) (P

This current study explored the effects of fine particulate matter (PM2.5) on deoxyribonucleic acid methylation in human bronchial epithelial cells. Human bronchial epithelial cells were exposed to PM2.5 for 24 h after which, deoxyribonucleic acid samples were extracted, and the differences between methylation sites were detected using methylation chips. Subsequent gene ontology functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed for the differential methylation sites. Functional epigenetic modules analysis of the overall differential methylation site interactions was also conducted. A total of 127 differential methylation sites in 89 genes were screened in the PM2.5 10 μg/ml group, of which 55 sites demonstrated increased methylation, with methylation levels decreasing in a further 72 sites. Following an exposure of 50 μg/ml PM2.5, a total of 238 differentially methylated sites were screened in 168 genes, of which methylation levels increased in 127 sites, and decreased in 111. KEGG analysis showed that the top 10 enrichment pathways predominantly involve hepatocellular carcinoma pathways and endometrial cancer pathways, whereas functional epigenetic modules analysis screened eight genes (A2M, IL23A, TPIP6, IL27, MYD88, ILE2B, NLRC4, TNF) with the most interactions. Our results indicate that exposure to PM2.5 for 24 h in human bronchial epithelial cells induces marked changes in deoxyribonucleic acid methylation of multiple genes involved in apoptosis and carcinogenesis pathways, these findings can provide a new direction for further study of PM2.5 carcinogenic biomarkers.

DNA methylation is one of the most extensively studied epigenetic modifications of genomic DNA. In recent years, sequencing of bisulfite-converted DNA, particularly via next-generation sequencing technologies, has become a widely popular method to study DNA methylation. This method can be readily applied to a variety of species, dramatically expanding the scope of DNA methylation studies beyond the traditionally studied human and mouse systems. In parallel to the increasing wealth of genomic methylation profiles, many statistical tools have been developed to detect differentially methylated loci (DMLs) or differentially methylated regions (DMRs) between biological conditions. We discuss and summarize several key properties of currently available tools to detect DMLs and DMRs from sequencing of bisulfite-converted DNA. However, the majority of the statistical tools developed for DML/DMR analyses have been validated using only mammalian data sets, and less priority has been placed on the analyses of invertebrate or plant DNA methylation data. We demonstrate that genomic methylation profiles of non-mammalian species are often highly distinct from those of mammalian species using examples of honey bees and humans. We then discuss how such differences in data properties may affect statistical analyses. Based on these differences, we provide three specific recommendations to improve the power and accuracy of DML and DMR analyses of invertebrate data when using currently available statistical tools. These considerations should facilitate systematic and robust analyses of DNA methylation from diverse species, thus advancing our understanding of DNA methylation.

A growing body of research has documented associations between adverse childhood environments and DNA methylation, highlighting epigenetic processes as potential mechanisms through which early external contexts influence health across the life course. The present study tested a complementary hypothesis: indicators of children's early internal, biological, and behavioral responses to stressful challenges may also be linked to stable patterns of DNA methylation later in life. Children's autonomic nervous system reactivity, temperament, and mental health symptoms were prospectively assessed from infancy through early childhood, and principal components analysis (PCA) was applied to derive composites of biological and behavioral reactivity. Buccal epithelial cells were collected from participants at 15 and 18 years of age. Findings revealed an association between early life biobehavioral inhibition/disinhibition and DNA methylation across many genes. Notably, reactive, inhibited children were found to have decreased DNA methylation of the DLX5 and IGF2 genes at both time points, as compared to non‐reactive, disinhibited children. Results of the present study are provisional but suggest that the gene's profile of DNA methylation may constitute a biomarker of normative or potentially pathological differences in reactivity. Overall, findings provide a foundation for future research to explore relations among epigenetic processes and differences in both individual‐level biobehavioral risk and qualities of the early, external childhood environment., This study examined whether children's early internal, biological, and behavioral responses to stress were predictive of DNA methylation later in life. Findings revealed an association between early life biobehavioral reactivity and DNA methylation in multiple genes measured at both 15 and 18 years of age. As such, DNA methylation may constitute a biomarker of normative or potentially pathological differences in reactivity.

Homeodomain-containing (HOX) factors such as the abdominal class homeodomain protein HOXA10 and the TALE-family protein PBX1 form coregulatory complexes and are potent transcriptional and epigenetic regulators of tissue morphogenesis. We have identified that HOXA10 and PBX1 are expressed in osteoprogenitors; however, their role in osteogenesis has not been established. To determine the mechanism of HOXA10-PBX-mediated regulation of osteoblast commitment and the related gene expression, PBX1 or HOX10 were depleted (shRNA or genetic deletion, respectively) or exogenously expressed in C3H10T1/2, bone marrow stromal progenitors, and MC3T3-E1 (preosteoblast) cells. Overexpression of HOXA10 increased the expression of osteoblast-related genes, osteoblast differentiation and mineralization; expression of PBX1 impaired osteogenic commitment of pluripotent cells and the differentiation of osteoblasts. In contrast, the targeted depletion of PBX1 by shRNA increased the expression of bone marker genes (osterix, alkaline phosphatase, BSP, and osteocalcin). Chromatin-associated PBX1 and HOXA10 were present at osteoblast-related gene promoters preceding gene expression, but PBX1 was absent from promoters during the transcription of bone-related genes, including osterix (Osx). Further, PBX1 complexes were associated with histone deacetylases normally linked with chromatin inactivation. Loss of PBX1 but not of HOXA10 from the Osx promoter was associated with increases in the recruitment of histone acetylases (p300), as well as decreased H3K9 methylation, reflecting transcriptional activation. We propose PBX1 plays a central role in attenuating the activity of HOXA10 as an activator of osteoblast-related genes and functions to establish the proper timing of gene expression during osteogenesis, resulting in proper matrix maturation and mineral deposition in differentiated osteoblasts.

The greatest burden of ill-health for adults in most societies relates to disorders of the cardiovascular system and to cancers [1]. These diseases are caused by lifestyle choices in which poor diet and relatively low levels of activity play a major role [1]. There is a large body of literature which shows that environmental exposures, including nutrition, play a significant role in the etiology of the disease, but there is variable susceptibility amongst individuals exposed to seemingly similar risk factors or environments. Cancer is a condition which results from a derangement in the cellular processes which regulate cell division, terminal differentiation and apoptosis, with damage to the genetic material of the cell being central. Exposures which lead to these derangements usually precede the appearance of the clinical disease by a prolonged period of time, often several decades [2]. While gene mutation has a role in the etiology of cancer, there is increasing evidence showing that epigenetic processes such as DNA methylation and covalent modification to histones are also involved [3]. Epigenetic changes of this kind represent potential for altered gene activity, and hence cellular dysregulation. However, the underlying propensity may only be manifest when the gene is exposed to an appropriate environmental signal with the direction of the response and nature of the cellular dysregulation a function of the specific epigenetic change [4, 5]. It has been known for many years that exposure of the individual to nutritional and other environmental challenges during critical periods of early development can markedly affect later size, shape, structure, function and behavior. However, Barker et al. [6] were the first to provide clear evidence that there might also be a direct link between early nutritional exposure and risk of chronic disease, building the evidence that is supportive of a causal association [6, 7]. In this they have refined a new conceptual approach to the way in which we consider the evolution of this group of diseases based upon a new developmental model, the so called ‘fetal origins hypothesis’. Based initially on ecological observations and later on retrospective cohort studies, there is now a considerable body of epidemiological and experimental data that supports the hypothesis. In the earlier observations, the size and shape of the baby at birth was shown to be related to the risk during adult life of coronary heart disease, hypertension, stroke, type 2 diabetes, obesity and some cancers [6]. These relations were shown to be graded across the usual range of birth weights seen in the population and not a special feature of very high or very low birth weight, indicating that they might be a consequence of the usual range of exposure found within a population [4, 7]. The results have been reproduced across a number of populations, and although there may be some debate around the details, the general principal appears to apply widely [4, 6, 7].

The influence of epigenetic alterations during cancer has gained increasing attention over the recent years and has resulted in a paradigm shift in our understanding of mechanisms leading to cancer susceptibility. These features are potentially reversible and may affect genomic stability and expression of genes, including tumor suppressor genes and oncogenes. The reversible acetylation of histones is an important mechanism of gene regulation. Targeting the epigenome, including the use of histone deacetylase (HDAC) inhibitors, is a novel strategy for cancer chemoprevention. We have found that sulforaphane (SFN), a compound found in cruciferous vegetables, inhibits HDAC activity in human colorectal and prostate cancer cells. The ability of SFN to target aberrant acetylation patterns, in addition to effects on phase 2 enzymes, may make it an effective chemoprevention agent. Other dietary agents such as butyrate, allyl sulfides and organoselenium compounds have also shown promise as HDAC inhibitors. These studies are significant because of the potential to qualify or change recommendations for high-risk cancer patients, thereby increasing their survival through simple dietary choices, such as incorporating easily accessible foods into a patient’s diet. The work to date provides a scientific foundation for future large-scale human clinical intervention studies with dietary agents that affect the epigenome.