Defective ferritinophagy and imbalanced iron metabolism in PBDE-47-triggered neuronal ferroptosis and salvage by Canolol.

The brominated flame retardant 2,2',4,4'-tetrabromodiphenyl ether (PBDE-47) is a ubiquitous environmental pollutant that causes neurotoxicity. However, incomplete understanding of the underlying mechanisms has hampered the development of effective intervention strategies. Oxidative stress and related cell death are the modes of action for PBDE-47 neurotoxicity, which are also the characteristics of ferroptosis. Nonetheless, the role of ferroptosis in PBDE-47-induced neurotoxicity remains unclear. In the present study, we found that PBDE-47 triggered ferroptosis in neuron-like PC12 cells, as evidenced by intracellular iron overload, lipid peroxidation, and mitochondrial damage. This was confirmed by ferroptosis inhibitors including the lipid reactive oxygen species scavenger ferrostatin-1 and iron chelator deferoxamine mesylate. Mechanistically, PBDE-47 impaired ferritinophagy by disrupting nuclear receptor coactivator 4-mediated lysosomal degradation of the iron storage protein ferritin. Moreover, PBDE-47 disturbed iron metabolism by increasing cellular iron import via upregulation of transferrin receptor 1 and decreasing cellular iron export via downregulation of ferroportin 1 (FPN1). Intriguingly, rescuing lysosomal function by overexpressing cathepsin B (CatB) mitigated PBDE-47-induced ferroptosis by partially restoring dysfunctional ferritinophagy and enhancing iron excretion via the upregulation of FPN1. However, FPN1 knockdown reversed the beneficial effects of CatB overexpression on the PBDE-47-induced iron overload. Finally, network pharmacology integrated with experimental validation revealed that Canolol, the main phenolic compound in canola oil, protected against PBDE-47-evoked iron overload, resulting in ferroptosis by restoring defective ferritinophagy and improving abnormal iron metabolism via lowering iron uptake and facilitating iron excretion. Overall, these data suggest that ferroptosis is a novel mechanism of PBDE-47-induced neuronal death and that manipulation of ferritinophagy and iron metabolism via Canolol represents a promising therapeutic strategy.

Ethylbenzene induces hearing loss by triggering mitochondrial impairments and excess apoptosis in cochlear progenitor cells via suppressing the Wnt/ß-catenin signaling.

Ethylbenzene (EB) is widely distributed at low levels in the environment from vehicle emissions, industrial discharge, cigarette smoke, and in some food and consumer products. Evidence shows that EB exposure is associated with hearing loss, yet the mechanisms are unclear. This study aimed to explore the role of the Wnt/ß-catenin signaling pathway, which plays a key role during cochlear development, in EB-induced hearing loss. In vitro, we found that EB treatment decreased the viability of cochlear progenitor cells (CPCs), isolated from the cochleae of neonatal rats and crucial for cochlear hair cells generation and hearing construction, via inducing mitochondrial impairments and excessive apoptosis. These were accompanied by the inactivation of the Wnt/ß-catenin signaling cascade, as manifested by the decreased levels of related molecules ß-catenin, LEF-1 and Lgr5. These findings were further confirmed by knocking down ß-catenin and immunofluorescence analysis. Interestingly, adenovirus-mediated ß-catenin overexpression activated the Wnt/ß-catenin signaling network, alleviated mitochondrial impairments, reduced cell apoptosis, therefore promoting CPCs survival under EB treatment conditions. Finally, using adult Sprague-Dawley rats as an in vivo model with EB inhalation for 13 weeks, we found that exposure to EB decreased body weight gain, increased the hearing thresholds at different exposure stages, along with Wnt/ß-catenin signaling pathway suppression in cochlear tissue. More importantly, cochlear microinjection of recombinant lentivirus expressing ß-catenin significantly reversed EB-elicited these deleterious effects. Collectively, our results indicate that EB induces hearing loss by triggering mitochondrial impairments and excess apoptosis in CPCs via suppressing the Wnt/ß-catenin signaling, and provide clues for the possible therapy.

The association of high-fluoride and high-iodine combined exposure with dental fluorosis and goiter: a meta-analysis.

It is controversial that high-fluoride and high-iodine combined exposure affects the prevalence of dental fluorosis and goiter. The aim of this study was to explore the potential association between high-fluoride and high-iodine combined exposure with dental fluorosis and goiter. We retrieved relevant articles from PubMed, Cochrane Library, China National Knowledge Infrastructure, Wanfang Database and China Science and Technology Journal Database (VIP). The query format was 1 # "Fluorosis" OR "Fluoride," 2 # "Iodine" OR "Iodide," and 3 # 1 AND 2. A total of 20 papers were included in this study after independent review by two investigators. Our analysis showed that high-fluoride and high-iodine biphasic exposure was significantly associated with the prevalence of goiter (OR = 4.69, 95% CI 2.82-7.80, P < 0.001). The prevalence of dental fluorosis was also significantly raised (OR = 11.71, 95% CI 7.57-18.14, P < 0.001). Sensitivity analysis suggested that combined statistics of multiple studies were reliable. For goiter, subgroup analysis revealed study province, sample size and published year as sources of heterogeneity (P < 0.001). For dental fluorosis, only sample size was the impact factor of heterogeneity. As well, funnel plot, Begg's test and Egger's test suggested there was no publication bias (P > 0.05). Overall, our study demonstrates that high-fluoride and high-iodine combined exposure is a risk factor for occurrence of dental fluorosis and goiter. The chronic of high-fluoride and high-iodine combined exposure is a significant higher risk of disease than normal.

Changes and relationship of N6-methyladenosine modification and long non-coding RNAs in oxidative damage induced by cadmium in pancreatic ß-cells.

N6-methyladenosine (m6A) modification and m6A-modified Long non-coding RNAs (LncRNAs) play crucial roles in various pathological processes, yet their changes and relationship in cadmium-induced oxidative damage are largely unknown. Here, five m6A-modified LncRNAs (LncRNA-TUG1, LncRNA-PVT1, LncRNA-MALAT1, LncRNA-XIST, LncRNA-NEAT1), which have been evidenced to involve in oxidative damage, were selected and their binding proteins were submitted to bioinformatics analysis. Our analysis results showed that these five m6A-modified LncRNAs bound to different regulatory proteins of m6A modification, implicating that m6A modification on LncRNAs may synergistically control by multiple regulatory proteins. Furthermore, the detection data revealed that levels of m6A modification, methyltransferase-like 3 (METTL3) and fat mass and obesity-associated protein (FTO) were all significantly decreased in CdSO4-induced oxidative damage, which was demonstrated by increasing ROS accumulation and MDA contents as well as decreasing SOD activities. More importantly, LncRNA-MALAT1 and LncRNA-PVT1 indicated downward trend and showed positive relationship with m6A modification. Collectively, our results showed that m6A modification and m6A-modified LncRNAs may involve in oxidative damage induced by cadmium.

Emerging Roles of MicroRNAs and Long Noncoding RNAs in Cadmium Toxicity.

Metal cadmium (Cd) and its compounds are ubiquitous industrial and environmental pollutants and they have been believed to exert severe damage to multiple organs and tissues. MicroRNAs (miRNAs) and long noncoding RNAs (lncRNAs) are the two most common noncoding RNAs and have pivotal roles in various cellular and physiological processes. Since the importance of miRNAs and lncRNAs in Cd toxicity has been widely recognized, we focus our interests on the current researches of miRNAs and lncRNAs as well as their regulation roles in Cd toxicity. In this paper, the keywords "cadmium" in combination with "miRNA" or "LncRNA" or "noncoding RNA" was used to retrieve relevant articles in PubMed, EMbase, CNKI, Wan Fang, and CBM databases. The literatures which contained the above keywords and carried out in animals (in vivo and in vitro) have been collected, collated, analyzed, and summarized. Our summary results showed that hundreds of miRNAs and lncRNAs are involved in the Cd toxicity, which have been demonstrated as multiple organ injury, reproductive toxicity, malignant transformation, and abnormal repair of DNA damage. In this paper, we also discussed the blank in present research field of Cd toxicity as well as suggested some ideas for future study in Cd toxicity.