The interaction between miRNAs and hazardous materials

Toxic agents are broadly present in the environment, households, and workplaces. Contamination of food and drinking water with these agents results in entry of these materials to the body. The crosstalk between these agents and microRNAs (miRNAs) affects pathoetiology of several disorders. These agents can influence the redox status, release of inflammatory cytokines and mitochondrial function. Altered expression of miRNA is involved in the dysregulation of several pathophysiological conditions and signaling pathways. These molecules are also implicated in the adaption to environmental stimuli. Thus, the interactions between miRNAs and toxic materials might participate in the hazardous effects of these materials in the body. This review describes the effects of the toxic materials on miRNAs and the consequences of these interactions on the human health.


Introduction
Hazardous materials are radioactive substances and/or chemical compounds which can be harmful to individuals or animals and the environment upon exposure [1]. As chemical materials, they fall into a category such as cadmium, lead, mercury, arsenic, chromium, and asbestos [2][3][4][5]. The United States Environmental Protection Agency (USEPA) has considered some of them to be probable human carcinogen agents. These materials are found in drinking water [6], air [7], and food [8], and therefore they could be absorbed via dermal contact, ingestion, and/or inhalation, leading to damage to body organs such as the lungs, kidneys, and liver. Different levels of poisoning occur after exposure to such substances. For example, arsenic is a well-known carcinogenic agent and is strongly linked to the development of lung, bladder, liver, and kidney cancers [9,10]. Or, asbestos fibers, including chrysotile, are highly associated with the development of lung cancer, mesothelioma, and pulmonary fibrosis [11,12].
A number of studies have shown that development of several diseases such as hypertension, gastrointestinal disorders, and osteoporosis is resulted from long-term exposure to these materials [13][14][15][16][17]. It has been also reported that some of these hazardous agents such as mercury, lead, and cadmium could pass from the placenta and cause a disruption in the normal process of fetal development [18,19].
In recent years, scientists have focused on a wide range of molecular alterations and mechanisms involved in hazardous material-related diseases [20,21]. Their results have shown that these mentioned materials could affect normal cell function and lead to cell death via a number of mechanisms including DNA methylation, inflammation, oxidative stress, autophagy, and apoptosis [22,23]. However, among these mechanisms, it has been reported that microRNAs (miRNAs) are associated with multiple organ injuries [24,25]. miRNAs are categorized as a form of the molecules of non-coding RNAs with nearly ~22 nucleotides in length [26,27]. Although they are not involved in protein coding, they could modify target mRNAs via the posttranscriptional mechanism. Both genetic and epigenetic mechanisms could also regulate miRNAs expression [28]. In this regard, for example, in human bronchial epithelial cells (HBECs) exposed to arsenic, elevated promoter methylation has led to suppression of miR-200. Moreover, arsenic has caused malignant transformation via altering epithelial-mesenchymal transition (EMT) signaling pathways [29]. Moreover, in lung cancer asbestos could alter the miRNA expression, where the expression of some miR-NAs such as miR-202, miR-605, and miR-939 decreased, while the expression of several miRNAs, such as miR-96, let-7d/e, and/or miR-374a, increased [30]. In this review, we investigated the interaction of miRNAs and some important hazardous materials.

Interaction between miRNAs and arsenic compounds
Arsenic compounds have been used for treatment of leukemia. For instance, arsenic trioxide (As [2]O(3), ATO) has been used for treatment of acute promyelocytic leukemia. Gao et al. have assessed possible synergy between miR-15a/16-1 and ATO in K562 cells. They have reported that combination of miR-15a/16-1 and ATO induces growth suppression and apoptosis in these Bcr-Abl positive leukemic cells. Mechanistically, apoptosis is induced through regulation of mitochondrial functions. In fact, this process involves release of cytochrome c and loss of mitochondrial transmembrane potential. Yet, ATO and/or miR-15a/16-1 could not affect expression of Bcr-Abl in these cells. Besides, miR-15a/16-1 and ATO could induce apoptosis in Bcr-Abl negative leukemic cell lines and primary leukemic cells in a synergic manner [31]. Another study has shown that anti-miR-21 oligonucleotide (AMO-miR-21) and ATO inhibit growth of K562 cells and induce apoptosis and G1 arrest in these cells. Mechanistically, AMO-miR-21 induces sensitivity to ATO through induction of apoptosis via up-regulation of PDCD4 levels [32]. miRNAs expression has also been found to be altered after arsenic exposure participating in the arsenic-induced multiorgan damage. Upregulation of miR-155 has been shown to be involved in the arsenic induced skin injury. Moreover, expression levels of miR-21 and miR-145 have been found to be associated with liver damage, while levels of miR-191 have been linked with kidney damage (Fig. 1). Furthermore, miR-155 has can be used as a diagnostic marker for arsenic-induced skin damage. Moreover, miR-21 and miR-145 have been suggested as diagnostic markers for liver damage. Finally, miR-191 can be used as a diagnostic marker for kidney damage [33]. Table 1 summarizes the results of studies that evaluated interactions between miRNAs and arsenic compounds.

Interaction between miRNAs and cadmium compounds
Cadmium (Cd) is an important hazardous agent that has toxic effects on fish and aquatic animals. Expression profiling of miRNAs in cultured common carp (Cyprinus carpio L.) has shown differential expression of a number of miRNAs during Cd exposure. In fact, 7 and 16 miRNAs have been found to be up-regulated and down-regulated, respectively. miR-122, novel-miR6, miR-193a-3p and miR-27a-5p have been among differentially expressed miRNAs (Fig. 2a). Moreover, expressions of BAX, BAD, BAK, CASPASE9 and PIDD have been enhanced, while BCL2 expression has been reduced following Cd exposure. Changes in the expression levels of mentioned miRNAs might be involved in the oxidative stress-induced apoptosis following exposure to Cd [56]. Another study has demonstrated inflammation-related injury in the spleens of common carp following Cd exposure. In fact, 17 miRNAs have been up-regulated, while 6 miRNAs have been down-regulated. Theses miRNAs have been functionally related with NF-κB, Jak-STAT, MAPK, Th1 and Th2 cell differentiation, and Toll-like receptor signaling pathways [57]. Another experiments in rat ovarian granulosa cells has shown that Cd is cytotoxic to these cells affecting expression of a number of miRNAs. In fact, Cd-induced damage to these cells is mediated by mitochondrial apoptosis [57]. In mice animal model, miR-6769b-5p via sponging CCND-1 might involve in the proliferation of placental trophoblast treated with CdCl2. Furthermore, via modulating the miR-34a/Sirt1/p53 signaling pathway, cd can damage the kidneys of mice and can control the apoptosis and inflammation (Fig. 2b). Table 2 shows the interaction between miRNAs and Cd.  [52] (continued on next page)

Interaction between miRNAs and lead compounds
miR-106b-5p has been shown to be up-regulated by lead (Pb 2+ )induced stress. miR-106b-5p has been shown to bind with the 3′-UTR of XIAP to down-regulate expression of XIAP. Inhibition of miR-106b-5p has been shown to reverse the decrease in IAP levels and cell viability in Pb 2+ -treated HT-22 and PC12 cells. Cumulatively, regulation of XIAP by miR-106b-5p might be associated with Pb neurotoxicity [81]. Another study has detected high levels of miR-155 and low levels of miR-126 in Pb exposed women. Moreover, authors have reported a significant simple positive relationship between blood lead levels and serum levels of miR-155. On the other hand, blood lead levels have been inversely correlated with serum miR-126 levels. Taken together, epigenetic changes might be linked with Pb exposure and its effects on health [82]. Besides, the interaction between miR-137 and EZH2 has been shown to contribute to the genome-wide redistribution of H3K27me3 which is responsible for Pb-associated memory impairment [83]. Table 3. Interaction between miRNAs and Pb in different contexts.

Interaction between miRNAs and asbestos
Comparison of miRNA signature between malignant pleural mesothelioma and benign asbestos-associated pleural effusion has led to identification of several up-regulated miRNAs in the former condition, among them being hsa-miR-484, hsa-miR-320, hsa-let-7a, and hsa-miR-125a-5p. These miRNAs have the potential to discriminate these two conditions [90]. Another study has reported down-regulation of miR-30d is in the pleural malignant mesothelioma cell line NCI-H2452, in the plasma samples of asbestos-exposed persons, and in mesothelial cells exposed to asbestos. Up-regulation of miR-30d could inhibit   Both mentioned miRNAs via targeting HO-1 could lead to immunotoxicity in the carp's kidneys. [74] (continued on next page) proliferation, migration, and invasion pleural malignant mesothelioma cells and enhance their apoptosis without affecting cell cycle. Moreover, it could decrease vimentin and TWIST1 levels, and increase CDH1 levels in NCI-H2452 cells. Thus, miR-30d is related to asbestos exposure and suppresses migration and invasion of NCI-H2452 cells through regulation of epithelial-mesenchymal transition [91]. Moreover, extracellular vesicle-levels of miR-103a-3p and miR-30e-3p have been shown to discriminate malignant pleural mesothelioma from past asbestos exposure [92]. Table 4 shows interactions between miRNAs and asbestos.

Interaction between miRNAs and mercury
Exposure to mercury is regarded as a public health problem in the world. Hsa-miR-92a and hsa-miR-486 have been suggested as novel diagnostic markers for detection of occupational mercury poisoning. These two miRNAs have been found to be over-expressed in individuals exposed to occupational mercury. Over-expression of these miRNAs contributes to mercury toxicity through activation of NF-κB signaling via influencing expressions of KLF4 and Cezanne, respectively [98].
Another study has shown significant differences in the plasma levels of miR-124-3p, miR-125-5p, and miR-127-3p between patients with amalgam filling, dentists, and control group. Serum mercury concentration and plasma miR-125-5p and miR-127-3p levels have been positively correlated. Serum mercury has also been correlated with plasma miR-125-5p levels among dentists. This study shows the impact of amalgam filling in enhancement of serum mercury and plasma miRNA levels [99]. Besides, two distinct miRNA signatures have been reported to be activated upon neuronal differentiation and following MeHgCl-induced toxicity. Principally, exposure to MeHgCl could induce down-regulation of six out of the ten most up-regulated neuronal pathways in neural models. In fact, miRNAs expression profiling has been suggested as a possible way for evaluation of developmental neurotoxicity pathway [100]. Table 5 shows the interaction between miRNAs and mercury.
kind of cancer including lung cancer. Cr(VI) treatment can also increase expression of Nrf2, a redox sensitive transcription factor with protective effcets on normal cells. Mechanistically, expression of redox sensitive miRNAs miR-27a and miR-27b is ecreased after 1 month exposure to Cr (VI), leading to alteration sin levels of their target Nrf2. Taken together, suppression of miR-27a/b leads to up-regulation of Nrf2 at early and late stages of exposure to Cr(VI) [101]. Cr(VI) has also been found to induce malignant transformation in lung bronchial epithelium through ROS-dependent induction of miR-21-PDCD4 signals [102]. Table 6 shows the interaction between miRNAs and chromium compounds.

Interactions between miRNAs and beryllium sulfate
The carcinogenic material beryllium sulfate (BeSO4) can affect expression of a number of non-coding RNAs in human bronchial epithelial cells. This substance has been found to up-regulate expression of 36 circRNAs and down-regulate other 35 circRNAs in these cells.
[115] Table 8 Interaction between miRNAs, hazardous compounds, as well as antioxidants. miR-663b and regulating JAK/STAT signaling [107]. Another study has shown that BeSO4 increases expression of some inflammatory molecules, including IL-10, TNF-α, IFN-γ, iNOS, and COX-2. Most notably, expression of 179 miRNAs has also been found to be changed by this substance. A number of these miRNAs have been shown to contribute to the transcription regulation, or modulation of MAPK, and VEGF signaling pathways [108].

Interaction between miRNAs and fluoride
Expression of several miRNAs has been shown to be changed in rat renal cortex following subchronic exposure to fluoride. These miRNAs have been mainly associated with extracellular matrix-receptor interactions, Mucin type O-glycan synthesis and Gap junctions. Moreover, expressions of miRNAs involved in cancer and proliferation have been changed after exposure to fluoride [109]. Combination of fluoride and aluminum (FA) has been shown to trigger apoptosis of rat hippocampal neurons and NG108-15 cells, enhance expression of miR-34b-5p, and decrease levels of Gnai2, PKA, ERK and CREB. Notably, suppression of miR-34b-5p expression could ameliorate FA-associated apoptosis and changes in the expressions of mentioned genes. Besides, miR-34b-5p has been found to modulate expression Gnai2 through targeting its 3′-UTR, indicating that miR-34b-5p participate in FA-associated neuron apoptosis through negatively targeting Gnai2 and suppressing activity of PKA/ERK/CREB cascade [110].
Furthermore, fluoride has been demonstrated to affect expression of 35 miRNAs, particularly those associated with glycolipid metabolism in the liver. In fact, these miRNAs could mediate fluoride-induced disturbance in the glycolipid metabolism, possibly through affecting activity of insulin, PPAR, and FOXO pathways [111].

Interaction between miRNAs and a combination of hazardous compounds
A number of studies have compared the effects of different hazardous materials in cell lines or animal models. For instance, experiments in C57BL/6J WT mice have shown that arsenic has more potent effects in disruption of the INS-1 beta cell miRNA landscape thansignature compared with cadmium or manganese [112]. Meanwhile, mixture of As-Cd-Pb has been shown to induce cellular transformation through affecting expression of miR-222 and post-transcriptional regulation of Rad51c levels [113]. Another study has assessed the association between miRNA profile in the cervix during pregnancy and levels of lead and mercury. This study has reported negative associations between levels of 17 miRNAs and toenail mercury levels. Moreover, tibial bone lead levels have been associated with down-regulation of miR-575 and miR-4286. Taken together, miRNAs levels in the human cervix has been suggested as novel markers for maternal exposures during pregnancy [114]. Table 7 shows the interaction between miRNAs and a combination of hazardous compounds.

The effects of antioxidants on expression of miRNAs during exposure with hazardous compounds
Treatment with antioxidants can ameliorate the effects of hazardous materials on body organs through modulation of expression of miRNAs (Table 8). For instance, treatment with quercetin via inhibiting miR-21 could attenuate liver fibrosis and steatosis induced by cadmium [116]. Moreover, Se-Y via increasing the expression of miR-26a-5p could act against necroptosis induced by CdCl2 in the kidney of the chicken [117] (Fig. 3). Other examples are shown in Table 8.

Conclusions
Several compounds have been shown to affect expressions of miR-NAs, thus disturbing activity of several signaling pathways in different tissues and contributing to diverse disorders. The impacts of the environmental exposure to hazardous materials on the epigenome have attracted a substantial interest in the recent years. miRNAs as important regulators of gene expression are of considerable importance in this regard. Several miRNAs have been shown to be dysregulated during exposure to these toxic agents being responsible for alterations in the physiological processes after exposure to toxins. Therefore, expression profiling of miRNAs represents a possible route for determination of the effects of hazardous materials on the body organs. Since miRNAs are stable in the circulation and are protected from endogenous RNase, miRNAs are regarded as suitable blood-based biomarkers not only for detection of human diseases but also for estimation of the amount of exposure to hazardous materials. However, the underlying mechanisms of contribution of miRNAs in toxic effects of these materials have not been elucidated yet.
More research is needed to establish a reliable profile of miRNA alterations after exposure to each hazardous material. These putative welldefined miRNA signatures can be used for early detection of disorders being associated with these compounds. Examples of these disorders include cancers, neurodegenerative disorders and pulmonary disorders. In addition, identification of the altered miRNAs during exposure to toxins can help in design of novel therapeutic modalities for complex disorders that are associated with environmental exposure. Finally, certain antioxidants have been found to ameliorate the effects of hazardous materials, particularly CdCl2 and Pb on miRNAs profile, thus amending the organ impairment/dysfunction associated with hazardous materials. Future high throughput studies are needed to find the suitable antioxidant for amelioration of each condition. These antioxidants are expected to reverse the effects of these materials on body organs; thus, they can be prescribed for persons that environmental or occupational exposure to hazardous materials. The off-target effects of antioxidants should be assessed in future studies.

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Funding
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Authors' contributions
SGF wrote the draft and revised it. MT and EJ designed and supervised the study. SRA, BMH, SDO and HS collected the data and designed the figures and tables. All the authors read the submitted version and approved it.

Declaration of competing interest
The authors declare they have no conflict of interest.