Perfluorooctane sulfonic acid (PFOS) is a persistent environmental pollutant. Exposure to PFOS has been associated with abnormal fetal development. The long non-coding RNA (lncRNA) has been showed to play a role in fetal growth restriction (FGR), preeclampsia (PE) and other pregnancy complications. Whether the lncRNA contributes to PFOS-induced toxicity in the placenta remains unknown. In this study, we investigated the function of lncRNA MEG3 and its derived miR-770 in PFOS-induced placental toxicity. Pregnant mice received gavage administration of different concentrations of PFOS (0.5, 2.5, and 12.5 mg/kg/day) from GD0 to GD17, and HTR-8/SVneo cells were treated with PFOS in the concentrations of 0, 10⁻¹, 1, 10 μM. We found that expression levels of miR-770 and its host gene MEG3 were reduced in mice placentas and HTR-8/SVneo cells with exposure of PFOS. A significant hypermethylation was observed at MEG3 promoter in placentas of mice gestational-treated with PFOS. We also confirmed that MEG3 and miR-770 overexpression alleviated the cell growth inhibition induced by PFOS. Furthermore, PTX3 (Pentraxin 3) was identified as the direct target of miR-770 and it was enhanced after PFOS exposure. In summary, our results suggested that MEG3 alleviate PFOS-induced placental cell inhibition through MEG3/miR-770/PTX3 axis.

Ambient particulate air pollution is a risk factor for cardiovascular and respiratory disease, yet the biological mechanisms underlying this association are not well understood. The current study aimed to investigate the mediation role of microRNAs on the association between personal PM₂.₅ exposure and blood pressure and lung function. One hundred and twenty adults (60 truck drivers and 60 office workers) aged 18–46 years were assessed on the June 15, 2008 and at follow-up (1- to 2-weeks later). MicroRNAs were extracted from the peripheral blood samples. Compared to truck drivers, there is a significant increase in FEF₂₅₋₇₅, FEV₁, and FEV₁/FVC and a decrease in PM₂.₅ in office workers (all p < 0.05). According to the Bonferroni corrected threshold p-value < 6.81 × 10⁻⁵ (0.05/734) used, personal PM₂.₅ data showed a significant positive association with miR-644 after the adjustment for age, BMI, smoking status, and habitual alcohol use. The mediation effect of miR-644 on the association between personal PM₂.₅ exposure and FEF₂₅₋₇₅ [B (95%CI) = −1.342 (−2.810, −0.113)], PEF [B (95%CI) = -1.793 (−3.926, −0.195)], and FEV₁/FVC [B (95%CI) = −0.119‰ (−0.224‰, −0.026‰)] was significant only for truck drivers after the adjustment for covariates. There were no similar associations with blood pressure. These results demonstrate microRNAs to potentially mediate association of PM₂.₅ with lung function. Subsequent studies are needed to further elucidate the potential mechanisms of action by which the mediation effect of microRNAs is achieved with this process.

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.

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.

Ambient fine particulate matter (PM₂.₅) can change the expression profile of microRNAs (miRs), which may play important roles in mediating inflammatory responses. The present study attempts to investigate the roles of miR-146a-5p in regulating cytokine expression in a human monocytic leukemia cell line (THP-1). Four types of PM₂.₅ extracts obtained from Beijing, China, were subjected to cytotoxic tests in THP-1 cells. These four PM₂.₅ extracts included two water extracts collected from non-heating and heating season (WN and WH), and two organic extracts from non-heating and heating season (DN and DH). Firstly, the four PM₂.₅ extracts caused cytotoxicity, oxidative stress responses, cytokine gene expressions and interleukin 8 (IL-8) release in THP-1 cells, with WH showing the highest cytotoxicity, WN showing the highest oxidative stress and inflammatory responses. Additionally, we observed expression of miR-146a-5p was significantly increased, with the maximal response of six folds in WN group. Cellular autophagy was initiated by PM₂.₅ indicated by related protein and gene expressions. Both RNA interference and autophagy inhibitor were applied to interrupt autophagy process in THP-1 cells. Autophagy dysfunction could alleviate IL-8 expression, suggesting autophagy process regulated cytokine expression and inflammatory response caused by PM₂.₅. A chemical inhibitor was applied to inhibit the function of miR-146a-5p, and then the expressions of IL-8 and autophagic genes were significantly aggravated. Meanwhile, two target genes of miR-146a-5p, interleukin-1 associated-kinase-1 (IRAK1) and tumor-necrosis factor receptor-associated factor-6 (TRAF6) were increased dramatically, which also played important roles in regulation of autophagy. These data suggested miR-146a-5p negatively modulated cytokine expression caused by PM₂.₅ via autophagy process through the target genes of IRAK1 and TRAF6. Our findings raised the concerns of the changes of miR expression profile and following responses caused by PM₂.₅.

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.

An increasing number of findings from epidemiological studies support associations between exposure to air pollution and the onset of several diseases, including pulmonary, cardiovascular and neurodegenerative diseases, and malignancies. However, intermediate, and potentially mediating, biological mechanisms associated with exposure to air pollutants are largely unknown. Previous studies on the human exposome have shown that the expression of certain circulating microRNAs (miRNAs), regulators of gene expression, are altered upon exposure to traffic-related air pollutants. In the present study, we investigated the relationship between particulate matter (PM) smaller than 2.5 μm (PM₂.₅), PM₂.₅ absorbance (as a proxy of black carbon and soot), and ultrafine-particles (UFP, smaller than 0.1 μm), measured in healthy volunteers by 24 h personal monitoring (PEM) sessions and global expression levels of peripheral blood miRNAs. The PEM sessions were conducted in four European countries, namely Switzerland (Basel), United Kingdom (Norwich), Italy (Turin), and The Netherlands (Utrecht). miRNAs expression levels were analysed using microarray technology on blood samples from 143 participants. Seven miRNAs, hsa-miR-24-3p, hsa-miR-4454, hsa-miR-4763-3p, hsa-miR-425-5p, hsa-let-7d-5p, hsa-miR-502-5p, and hsa-miR-505-3p were significantly (FDR corrected) expressed in association with PM₂.₅ personal exposure, while no significant association was found between miRNA expression and the other pollutants. The results obtained from this investigation suggest that personal exposure to PM₂.₅ is associated with miRNA expression levels, showing the potential for these circulating miRNAs as novel biomarkers for air pollution health risk assessment.

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.

Diclofenac (DCF) has been recognized as an emerging contaminant in aquatic environments. Though many studies have investigated the toxic effects of DCF in human and mammals, limited information is available for the responses of genes associated with detoxification metabolisms in non-target aquatic organisms such as fish. In the present study, a small benthic fish Mugilogobius abei, was chosen as the test organism and the effects of DCF on detoxification-related genes at transcriptional level in M. abei were investigated. Partial cDNAs of pregnane-X-receptor (pxr), cytochrome P450 3A (cyp 3a) and alpha-gst were cloned firstly. The responses of cyp 1a, cyp 3a, alpha-gst and p-gp genes and associated microRNAs expressions were measured under different concentrations of DCF exposure (0.5, 5, 50, 500 μg/L) for 24 h and 168 h. Induction of cyp 1a, cyp 3a, alpha-gst, p-gp and pxr mRNA expressions was observed under DCF exposure for different time. Positive concentration-response relationships between DCF concentrations and cyp 1a as well as alpha-gst mRNA expression were observed under DCF exposure for 24 h. The similar trend between pxr mRNA expression and cyp 3a gene expression suggested the role of pxr in regulation of its downstream detoxification genes involved in DCF detoxification in M. abei. The negative correlation between miR-27a and p-gp expression under DCF exposure for 24 h indicated the role of miRNA in post transcriptional regulation on detoxification-related genes mRNAs in M. abei exposed to DCF. Overall, DCF exposure, even at environmental levels, may interrupt the responses of the detoxification genes in M. abei, which may affect the response of the exposed organism to other pollutants. This work provides implications on the bio-monitoring and risk assessment of DCF in aquatic ecosystems by using of local native fish species.

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.