The present study aims to determine the associations of multiple plasma metal levels and plasma microRNAs (miRNAs) with diabetes risk, and further explore the mediating effects of plasma miRNAs on the associations of plasma metal with diabetes risk. We detected plasma levels of 23 metals by inductively coupled plasma mass spectrometry (ICP-MS) among 94 newly diagnosed and untreated diabetic cases and 94 healthy controls. The plasma miRNAs were examined by microRNA Array screening and Taqman real-time PCR validation among the same study population. The multivariate logistic regression models were employed to explore the associations of plasma metal and miRNAs levels with diabetes risk. Generalized linear regression models were utilized to investigate the relationships between plasma metal and plasma miRNAs, and mediation analysis was used to assess the mediating effects of plasma miRNAs on the relationships between plasma metals and diabetes risk. Plasma aluminum (Al), titanium (Ti), copper (Cu), zinc (Zn), selenium (Se), rubidium (Rb), strontium (Sr), barium (Ba), and Thallium (Tl) levels were correlated with elevated diabetic risk while molybdenum (Mo) with decreased diabetic risk (P < 0.05 after FDR multiple correction). MiR-122–5p and miR-3141 were positively associated with diabetes risk (all P < 0.05). Ti, Cu, and Zn were positively correlated with miR-122–5p (P = 0.001, 0.028 and 0.004 respectively). Ti, Cu, and Se were positively correlated with miR-3141 (P = 0.003, 0.015, and 0.031 respectively). In addition, Zn was positively correlated with miR-193b-3p (P = 0.002). Ti was negatively correlated with miR-26b-3p (P = 0.016), while Mo and miR-26b-3p were positively correlated (P = 0.042). In the mediation analysis, miR-122–5p mediated 48.0% of the association between Ti and diabetes risk. The biological mechanisms of the association are needed to be explored in further studies.

Several studies have reported an association between residential surrounding particulate matter with an aerodynamic diameter ≤2.5 μm (PM₂.₅) and coronary heart disease (CHD). However, the underlying biological mechanism remains unclear. To fill this research gap, this study enrolled a residentially stable sample of 942 patients with CHD and 1723 controls. PM₂.₅ concentration was obtained from satellite-based annual global PM₂.₅ estimates for the period 1998–2019. MicroRNA microarray and pathway analysis of target genes was performed to elucidate the potential biological mechanism by which PM₂.₅ increases CHD risk. The results showed that individuals exposed to high PM₂.₅ concentrations had higher risks of CHD than those exposed to low PM₂.₅ concentrations (odds ratio = 1.22, 95% confidence interval: 1.00, 1.47 per 10 μg/m³ increase in PM₂.₅). Systolic blood pressure mediated 6.6% of the association between PM₂.₅ and CHD. PM₂.₅ and miR-4726-5p had an interaction effect on CHD development. Bioinformatic analysis demonstrated that miR-4726-5p may affect the occurrence of CHD by regulating the function of RhoA. Therefore, individuals in areas with high PM₂.₅ exposure and relative miR-4726-5p expression have a higher risk of CHD than their counterparts because of the interaction effect of PM₂.₅ and miR-4726-5p on blood pressure.

There is a scarcity of studies on the interactions between heavy metals and non-alcoholic fatty liver disease (NAFLD). Using a variety of statistical approaches, we investigated the impact of three common heavy metals on liver enzymes and NAFLD markers in a Korean adult population. We observed that cadmium, mercury, and lead all demonstrated positive correlations with liver enzymes and NAFLD indices. Our findings were mostly robust in secondary analysis, which included three novel mixture modeling approaches (WQS, qgcomp, and BKMR) as well as in silico investigation of molecular mechanisms (genes, miRNAs, biological processes, pathways, and illnesses). The 16 genes interacted with a mixture of heavy metals, which was linked to the development of NAFLD. Co-expression was discovered in nearly half of the interactions between the 18 NAFLD-linked genes. Key molecular pathways implicated in the pathogenesis of NAFLD generated by the heavy metal combination include activated oxidative stress, altered lipid metabolism, and increased cytokines and inflammatory response. Heavy metal exposure levels were related to liver enzymes and NAFLD indices, and cutoff criteria were revealed. More studies are needed to validate our findings and gain knowledge about the effects of chronic combined heavy metal exposure on adult and child liver function and the likelihood of developing NAFLD. To reduce the occurrence of NAFLD, early preventative and regulatory actions (half-yearly screening of workers at high-risk facilities; water filtration; avoiding excessive amounts of seafood, etc.) should be taken.

Arsenic is a potent toxicant, and long-term exposure to inorganic arsenic causes lung damage. M2 macrophages play an important role in the pathogenesis of pulmonary fibrosis. However, the potential connections between arsenic and M2 macrophages in the development of pulmonary fibrosis are elusive. C57BL/6 mice were fed with drinking water containing 0, 10 and 20 ppm arsenite for 12 months. We have found that, in lung tissues of mice, arsenite, a biologically active form of arsenic, elevated H19, c-Myc, and Arg1; decreased let-7a; and caused pulmonary fibrosis. For THP-1 macrophages (THP-M) and bone-marrow-derived macrophages (BMDMs), 8 μM arsenite increased H19, c-Myc, and Arg1; decreased let-7a; and induced M2 polarization of macrophages, which caused secretion of the fibrogenic cytokine, TGF-β1. Down-regulation of H19 or up-regulation of let-7a reversed the arsenite-induced M2 polarization of macrophages. Arsenite-treated THP-M and BMDMs co-cultured with MRC-5 cells or primary lung fibroblasts (PLFs) elevated levels of p-SMAD2/3, SMAD4, α-SMA, and collagen I in lung fibroblasts and resulted in the activation of lung fibroblasts. Knockout of H19 or up-regulation of let-7a in macrophages reversed the effects. The results indicated that H19 functioned as an miRNA sponge for let-7a, which was involved in arsenite-induced M2 polarization of macrophages and induced the myofibroblast differentiation phenotype by regulation of c-Myc. In the sera of arseniasis patients, levels of hydroxyproline and H19 were higher, and levels of let-7a were lower than levels in the controls. These observations elucidate a possible mechanism for arsenic exposure-induced pulmonary fibrosis.

Microcystin-LR (MC-LR) and glyphosate (GLY) have been classified as a Group 2B and Group 2A carcinogens for humans, respectively, and frequently found in aquatic ecosystems. However, data on the potential hazard of MC-LR and GLY exposure to the fish gut are relatively scarce. In the current study, a subacute toxicity test of zebrafish exposed to MC-LR (35 μg L⁻¹) and GLY (3.5 mg L⁻¹), either alone or in combination was performed for 21 d. The results showed that MC-LR or/and GLY treatment reduced the mRNA levels of tight junction genes (claudin-5, occludin, and zonula occludens-1) and altered the levels of diamine oxidase and D-lactic, indicating increased intestinal permeability in zebrafish. Furthermore, MC-LR and/or GLY treatment remarkably increased the levels of intestinal IL-1β and IL-8 but decreased the levels of IL-10 and TGF-β, indicating that MC-LR and/or GLY exposure induced an inflammatory response in the fish gut. MC-LR and/or GLY exposure also activated superoxide dismutase and catalase, generally upregulated the levels of p53, bax, bcl-2, caspase-3, and caspase-9, downregulated the levels of caspase-8 and caused notable histological injury in the fish gut. Moreover, MC-LR and/or GLY exposure also significantly altered the microbial community in the zebrafish gut and the expression of miRNAs (miR-146a, miR-155, miR-16, miR-21, and miR-223). Chronic exposure to MC-LR and/or GLY can induce intestinal damage in zebrafish, and this study is the first to demonstrate an altered gut microbiome and miRNAs in the zebrafish gut after MC-LR and GLY exposure.

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.

Arsenic, a class I human carcinogen, is ubiquitously found throughout the environment and around the globe, posing a great public health concern. Notably, Bangladesh and regions of West Bengal have been found to have high levels (0.5–4600 μg/L) of arsenic drinking water contamination, and approximately 50 million of the world’s 200 million people chronically exposed to arsenic in Bangladesh alone. This study was carried out to examine genome-wide gene expression changes in individuals chronically exposed to arsenic-contaminated drinking water. Our study population includes twenty-nine Bangladeshi female participants with urinary arsenic levels ranging from 22.32 to 1828.12 μg/g creatinine. RNA extracted from peripheral blood mononuclear cells (PBMCs) were evaluated using RNA-Sequencing analysis. Our results indicate that a total of 1,054 genes were significantly associated with increasing urinary arsenic levels (FDR p < 0.05), which include 418 down-regulated and 636 up-regulated genes. Further Ingenuity Pathway Analysis revealed potential target genes (DAPK1, EGR2, APP), microRNAs (miR-155, -338, −210) and pathways (NOTCH signaling pathway) related to arsenic carcinogenesis. The selection of female-only participants provides a homogenous study population since arsenic has significant sex dependent effects, and the wide exposure range provides new insight for key gene expression changes that correlate with increasing urinary arsenic levels.

Exposure to atmospheric particulate matter (PM) has been related to the increasing incidence and mortality of pulmonary diseases, where microRNAs (miRNAs) play significant roles in these biological and pathological processes. In the present study, we found that miR-382-5p played an anti-inflammatory role in pulmonary inflammation induced by fine particulate matter (PM₂.₅) or diesel exhaust particles (DEPs) in vitro and in vivo. The expression level of miR-382-5p was downregulated, while its target gene, namely CXCL12, was elevated in HBE cells after exposure to PM₂.₅ or DEPs. Mechanistically, PM₂.₅ or DEPs exposure increased CXCL12/MMP9 expression via miR-382-5p inhibition, subsequently triggered pulmonary inflammation. Furthermore, antagonizing the function of CXCL12 significantly reduced the expression of MMP9 and local inflammation induced by PM₂.₅ or DEPs. PM₂.₅ or DEPs caused apoptosis and G1 phase arrest could be partially restored by overexpression of miR-382-5p and antagonism of CXCL12. In a murine model, enhanced miR-382-5p expression effectively reduced expression levels of CXCL12, MMP9 and inflammatory cytokines, hereby protected lung tissues against PM₂.₅ or DEPs-induced lesions. Collectively, the miR-382-5p/CXCL12/MMP9 pathway may provide a mechanism, which mediates inflammatory response to PM₂.₅ or DEPs exposure.

Numerous recent studies have underlined the crucial players of noncoding RNAs (ncRNAs), i.e., microRNAs(miRNAs), long noncoding RNAs(lncRNAs) and circle RNAs(circRNAs) participating in genotoxic responses induced by a wide variety of environmental genotoxicants consistently. Genotoxic-derived ncRNAs provide us a new epigenetic molecular–ecological network (MEN) insights into the underlying mechanisms regarding genotoxicant exposure and genotoxic effects, which can modify ncRNAs to render them “genotoxic” and inheritable, thus potentially leading to disease risk via epigenetic changes. In fact, the spatial structures of ncRNAs, particularly of secondary and three-dimensional structures, diverse environmental genotoxicants as well as RNA splicing and editing forma dynamic pool of ncRNAs, which constructs a MEN in cells together with their enormous targets and interactions, making biological functions more complicated. We nonetheless suggest that ncRNAs have both beneficial(positive) and harmful(negative) effects, i.e., are “double-edged” in regulating genotoxicant toxic responses. Understanding the “double-edged” effects of ncRNAs is of crucial importance for our further comprehension of the pathogenesis of human diseases induced by environmental toxicants and for the construction of novel prevention and therapy targets. Furthermore, the MEN formed by ncRNAs and their interactions each other as well as downstream targets in the cells is important for considering the active relationships between external agents (environmental toxicants) and inherent genomic ncRNAs, in terms of suppression or promotion (down- or upregulation), and engineered ncRNA therapies can suppress or promote the expression of inherent genomic ncRNAs that are targets of environmental toxicants. Moreover, the MEN would be expected to be would be applied to the mechanistic explanation and risk assessment at whole scene level in environmental genotoxicant exposure. As molecular biology evolves rapidly, the proposed MEN perspective will provide a clearer or more comprehensive holistic view.

Arsenic induced senescence (AIS) has been identified in the population of West Bengal, India very recently. Also there is a high incidence of arsenic induced peripheral neuropathy (PN) throughout India. However, the epigenetic regulation of AIS and its contribution in arsenic induced PN remains unexplored. We recruited seventy two arsenic exposed and forty unexposed individuals from West Bengal to evaluate the role of senescence associated miRNAs (SA-miRs) in AIS and their involvement if any, in PN. The downstream molecules of the miRNA associated with the disease outcome, was also checked by immuoblotting. In vitro studies were conducted with HEK 293 cells and sodium arsenite exposure. Our results show that all the SA-miRs were upregulated in comparison to unexposed controls. miR-29a was the most significantly altered, highest expression being in the arsenic exposed group with PN, suggesting its association with the occurrence of PN. We looked for the expression of peripheral myelin protein 22 (PMP22), a specific target of miR-29a associated with myelination and found that both in vitro and in vivo results showed over-expression of the protein. Since this was quite contrary to miRNA regulation, we checked for intermediate players β-catenin and GSK-3β upon arsenic exposure which affects PMP22 expression. We found that β-catenin was upregulated in vitro and was also highest in the arsenic exposed group with PN while GSK-3β followed the reverse pattern. Our findings suggest that arsenic exposure alters the expression of SA-miRs and the mir-29a/beta catenin/PMP22 axis might be responsible for arsenic induced PN.