Excess fluoride in drinking water is an environmental issue of increasing worldwide concern, because of its adverse effect on human health. Skeletal fluorosis caused by chronic exposure to excessive fluoride is a metabolic bone disease characterized by accelerated bone turnover accompanied by aberrant activation of osteoblasts. It is not clear whether Wnt/β-catenin signaling, an important signaling pathway regulating the function of osteoblasts, mediates the pathogenesis of skeletal fluorosis. A cross-sectional case-control study was conducted in Tongyu County, Jilin Province, China showed that fluoride stimulated the levels of OCN and OPG, resulting in accelerated bone turnover in patients with skeletal fluorosis. To investigate the influence of fluoride on Wnt/β-catenin signaling pathway, 64 male BALB/c mice were allotted randomly to four groups and treated with deionized water containing 0, 55, 110 and 221 mg/L NaF for 3 months, respectively. The results demonstrated that fluoride significantly increased mouse cancellous bone formation and the protein expression of Wnt3a, phospho-GSK3β (ser 9) and Runx2. Moreover, partial correlation analysis indicated that there was no significant correlation between fluoride exposure and Runx2 protein levels, after adjusting for β-catenin, suggesting that β-catenin might play a crucial role in fluoride-induced aberrant osteogenesis. In vivo, viability of SaoS2 cells was significantly facilitated by 4 mg/L NaF, and fluoride could induce the abnormal activation of Wnt/β-catenin signaling, the expression of its target gene Runx2 and significantly increased Tcf/Lef reporter activity. Importantly, inhibition of β-catenin suppressed fluoride-induced Runx2 protein expression and the osteogenic phenotypes. Taken together, the present study provided in vivo and in vitro evidence reveals a potential mechanism for fluoride-induced aberrant osteoblast activation and indicates that β-catenin is the pivot molecule mediating viability and differentiation of osteoblasts and might be a therapeutic target for skeletal fluorosis.

Although the incidence of Crohn’s disease has increased worldwide over the past 30 years, the disorder’s exact causes and physiological mechanisms have yet to be determined. Given that genetic determinants alone do not explain the development of Crohn’s disease, there is growing interest in “environmental” determinants. In medical science, the term “environment” refers to both the ecological and social surroundings; however, most published studies have focused on the latter. In environmental and exposure sciences, the term “environment” mostly relates to contamination of the biotope. There are many unanswered questions on how environmental hazards might contribute to the pathogenesis of Crohn’s disease. Which pollutants should be considered? Which mechanisms are involved? And how should environmental contamination and exposure be evaluated? The objective was to perform a systematic review of the literature on Crohn’s disease and environmental contamination. We searched the PubMed, Google Scholar, Scopus, ISI Web of Science and Prospero databases. We considered all field studies previous to April 2019 conducted on human health indicators, and evaluating exposure to all type of physical, biological and chemical contamination of the environment. The lack of clear answers to date can be ascribed to the small total number of field studies (n = 16 of 39 publications, most of which were conducted by pioneering medical scientists), methodological differences, and the small number of contaminants evaluated. This make it impossible to conduct a coherent and efficient meta-analysis. Based on individual analysis of available studies, we formulated five recommendations on improving future research: (i) follow up the currently identified leads - especially metals and endocrine disruptors; (ii) explore soil contamination; (iii) gain a better knowledge of exposure mechanisms by developing transdisciplinary studies; (iv) identify the most plausible contaminants by developing approaches based on the source-to-target distance; and (v) develop registries and cohort-based analyses.

Fine particulate matter (PM₂.₅) is an essential risk factor of chronic obstructive pulmonary disease (COPD). Recent studies showed weak association between PM₂.₅ and COPD incidence, but smokers who exposed to higher PM₂.₅ concentration had more opportunity to gain COPD. Cigarette smoking is the most important risk factor of COPD. Thus, we hypothesized: the role of PM₂.₅ played on cigarette-inflamed airways was more significant than normal airways. The study firstly established an animal model of C57BL/6J mice with cigarette smoke exposure and PM₂.₅ orotracheal administration. After calculating pathological scores, mean linear intercept and mean alveolar area, we found PM₂.₅ aggravated pathological injury of cigarette-inflamed lungs, but the injury on normal lungs was not significant. Meanwhile, inflammatory factors as T-bet, IFN-γ and IL-1α were tested using qRT-PCR and ELISA. The results showed PM₂.₅ aggravated inflammation of cigarette-inflamed lungs, but the effect on normal lungs was not significant. The most important pathogenesis of COPD is abnormal apoptosis in airway epithelium, due to oxidative stress following long-term exposure to cigarette smoke. Then, apoptotic responses were detected in lungs. TUNEL analysis demonstrated that PM₂.₅ promoted DNA fragmentation of cigarette-inflamed lungs, but the effect on normal lungs was not significant. Western-blot and immunohistochemistry showed caspase activated significantly in PM₂.₅-cigarette smoke exposed lungs and activated caspase 3 located mainly on bronchial epithelium. Next, human bronchial epithelial cells were cultured treated with cigarette smoke solution (CSS) with or without PM₂.₅. Z-VAD-FMK, a pan-caspase inhibitor, was used to suppress the activation of caspases. After analyzing cell viability, DNA fragmentation, mitochondrial activities and caspase activities, the results clarified that PM₂.₅ aggravated apoptosis in cigarette-inflamed bronchial epithelial cells and the responses could be suppressed by Z-VAD-FMK. Our results gave a new idea about the mechanism of PM₂.₅ on COPD and inferred cigarette-inflamed airways were more vulnerable to PM₂.₅ than normal airways.

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.

Noise is associated with poor reproductive health. A number of animal studies have suggested the possible effects of exposure to high noise levels on fertility; to date, a little such research has been performed on humans.We examined an association between daytime and nocturnal noise exposures over four years (2002–2005) and subsequent male infertility.We used the National Health Insurance Service-National Sample Cohort (2002–2013), a population-wide health insurance claims dataset. A total of 206,492 males of reproductive age (20–59 years) with no history of congenital malformations were followed up for an 8-year period (2006–2013). Male infertility was defined as per ICD-10 code N46. Data on noise exposure was obtained from the National Noise Information System. Exposure levels of daytime and night time noise were extrapolated using geographic information systems and collated with the subjects' administrative district code, and individual exposure levels assigned.During the study period, 3293 (1.6%) had a diagnosis of infertility. Although there was no association of infertility with 1-dB increments in noise exposure, a non-linear dose-response relationship was observed between infertility and quartiles of daytime and night time noise after adjustment for confounding variables (i.e., age, income, residential area, exercise, smoking, alcohol drinking, blood sugar, body mass index, medical histories, and particulate pollution). Based on WHO criteria, adjusted odds for infertility were significantly increased (OR = 1.14; 95% CI, 1.05–1.23) in males exposed to night time noise ≥ 55 dB.We found a significant association between exposure to environmental noise for four years and the subsequent incidence of male infertility, suggesting long-term exposure to noise has a role in pathogenesis of male infertility.

Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by inflammation and impaired tissue regeneration, and is reported as the fourth leading cause of death worldwide by the Centers for Disease Control and Prevention (CDC). Environmental pollution and specifically motor vehicle emissions are known to play a role in the pathogenesis of COPD, but little is still known about the molecular mechanisms that are altered following diesel exhaust particles (DEP) exposure. Here we used lung organoids derived from co-culture of alveolar epithelial progenitors and fibroblasts to investigate the effect of DEP on the epithelial-mesenchymal signaling niche in the distal lung, which is essential for tissue repair. We found that DEP treatment impaired the number as well as the average diameter of both airway and alveolar type of lung organoids. Bulk RNA-sequencing of re-sorted epithelial cells and fibroblasts following organoid co-culture shows that the Nrf2 pathway, which regulates antioxidants' activity, was upregulated in both cell populations in response to DEP; and WNT/β-catenin signaling, which is essential to promote epithelial repair, was downregulated in DEP-exposed epithelial cells. We show that pharmacological treatment with anti-oxidant agents such as N-acetyl cysteine (NAC) or Mitoquinone mesylate (MitoQ) reversed the effect of DEP on organoids growth. Additionally, a WNT/β-catenin activator (CHIR99021) successfully restored WNT signaling and promoted organoid growth upon DEP exposure. We propose that targeting oxidative stress and specific signaling pathways affected by DEP in the distal lung may represent a strategy to restore tissue repair in COPD.

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.

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.

Cigarette smoke is an important indoor air pollutant which has deleterious effects on human health. Continued daily exposure to cigarette smoke has been attributed to the risk factor of ocular surface diseases. However, the mechanisms underlying the ocular surface damage are not fully elucidated. In this study, exposure to cigarette smoke extract (CSE) induced a dose- and time-dependent cytotoxicity in human corneal epithelial (HCE) cells, supported by the observation of reduced cell viability, increased apoptotic cells, elevated intracellular oxidative stress and loss of mitochondrial transmembrane potential. In addition, CSE exposure led to the impairment of proteostasis and autophagy, which resulted in the accumulation of ubiquitinated proteins as aggregates in peri-nuclear spaces. Furthermore, the autophagy inducer, cysteamine was shown to attenuate the CSE induced cell damage, oxidative stress and mitochondrial dysfunction in HCE cells. Moreover, cysteamine inhibited the formation of ubiquitin-positive aggregates around the peri-nuclear region, through regulating the autophagic activity of HCE cells. Similar to in vitro experiments, cigarette smoke induced proteostasis and autophagy impairment in corneal epithelial cells could be rescued by cysteamine in a cigarette smoke-exposed murine model. Therefore, this study may provide first evidence that dysfunction of autophagy contributes to the pathogenesis of ocular surface diseases associated with cigarette smoke exposure. Besides, it also suggests the potential therapeutic value of cysteamine in the prevention and treatment of cigarette smoke induced ocular surface injury.CSE induces cytotoxicity and accumulation of ubiquitinated proteins in HCE cells due to impairment of proteostasis and autophagy, which can be rescued by cysteamine.

Human exposure to neurotoxic pollutants (e.g. metals, pesticides and other chemicals) is recognized as a key risk factor in the pathogenesis of neurodegenerative disorders. Emerging evidence indicates that an alteration in autophagic pathways may be correlated with the onset of the neurotoxicity resulting from chronic exposure to these pollutants. In fact, autophagy is a natural process that permits to preserving cell homeostasis, through the seizure and degradation of the cytosolic damaged elements. However, when an excessive level of intracellular damage is reached, the autophagic process may also induce cell death. A correct modulation of specific stages of autophagy is important to maintain the correct balance in the organism. In this review, we highlight the critical role that autophagy plays in neurotoxicity induced by the most common classes of environmental contaminants. The understanding of this mechanism may be helpful to discover a potential therapeutic strategy to reduce side effects induced by these compounds.