Co-exposure to fluoride and arsenic disrupts intestinal flora balance and induces testicular autophagy in offspring rats.

While numerous studies have shown that fluoride or arsenic exposure may damage the reproductive system, there are few reports of co-exposure to fluoride and arsenic. In addition, the literature on autophagy and intestinal flora composition in reproductive toxicity studies of co-exposure to fluoride and arsenic is insufficient. In this study, we developed a rat model of fluoride and arsenic exposure via drinking water from pre-pregnancy to 90 days postnatal. Sprague-Dawley rats were randomly divided into sterile water control group, fluoride group (100 mg/L NaF), arsenic group (50 mg/L NaAsO2) and combined exposure group (100 mg/L NaF+50 mg/L NaAsO2). Our results showed that fluoride and arsenic exposure caused a reduction in testicular weight and significant pathological damage to tissue. We found that the levels of follicle-stimulating hormone, luteinizing hormone, and testosterone were reduced to varying degrees. Meanwhile experiments showed that fluoride and arsenic exposure can modulate autophagic flux, causing increased levels of Beclin1 and LC3 expression and decreased p62 expression. Analogously, by performing 16S sequencing of rat feces, we found 24 enterobacterial genera that differed significantly among the groups. Furthermore, the flora associated with testicular injury were identified by correlation analysis of hormonal indices and autophagy alterations with intestinal flora composition at the genus level, respectively. In summary, our study shows that fluoride and arsenic co-exposure alters autophagic flux in the testis, causes testicular injury, and reveals an association between altered intestinal flora composition and testicular injury.

Proteomics and transcriptomics jointly identify the key role of oxidative phosphorylation in fluoride-induced myocardial mitochondrial dysfunction in rats.

The regulation of mitochondrial function, which is dominated by oxidative phosphorylation (OXPHOs), is important in fluoride induced cardiovascular disease. Based on the previous study of fluoride-induced mitochondrial structure and membrane potential abnormalities, this study integrated ITRAQ protein quantification and RNA-Seq methods to analyze the sequencing data of rat myocardial tissue under fluoride exposure (0, 30, 60 and 90 mg/L). A total of 22 differentially expressed genes associated with the OXPHOs pathway were screened by Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) co-enrichment analysis, and were localizated by Interaction Network and calculated inter-genes and inter-omics correlations by Pearson correlation. In general, fluoride exposure can down-regulate genes related OXPHOs, particularly affecting the assembly of the complex I including Ndufa10, resulting in abnormal mitochondrial ATP synthesis and reduced myocardial energy supply. Most importantly, this study shows that the enriched information from the proteomics can explain the change process of energy production, but the specific molecules involved in energy supply cannot be obtained via transcriptomics information alone. Based on the results of transcriptional and protein analysis, our findings contribute to an innovative understanding of the pathways and molecular changes of myocardial injury induced by fluorosis.

Effects of arsenic exposure on lipid metabolism: a systematic review and meta-analysis.

Lipid metabolism dysfunction is a risk factor for cardiovascular diseases. Reportedly, arsenic exposure could affect lipid metabolism, but this finding remains controversial. Herein, we updated and reevaluated evidence regarding the relationship between arsenic exposure and lipid metabolism. Electronic and manual searches were performed to determine the effect of arsenic exposure on lipid metabolism from inception up to 30 November 2019. Overall, five studies were included in our meta-analysis. Two reviewers independently extracted information. Standardized mean difference (SMD) and 95% confidence intervals (CI) were used to analyze the combined effects of four indicators related to lipid metabolism (total cholesterol [TC], triglyceride [TG], high-density lipoprotein [HDL], low-density lipoprotein [LDL]). Afterwards, subgroup and sensitivity analyses were performed to explore the source of heterogeneity. Publication bias was tested using funnel plots and Begg's test. In this study, we observed that arsenic exposure can affect lipid metabolism by reducing serum HDL levels and increasing serum LDL levels. Following subgroup analysis, the arsenic concentration appeared to affect lipid metabolism. Funnel plot and Begg's test suggested no asymmetry. In conclusion, we recommend that potential influencing factors, including age, exposure time, and multiple concentration gradients, should be considered to further explore the relationship between arsenic exposure and lipid metabolism.

Caloric restriction increases the resistance of aged heart to myocardial ischemia/reperfusion injury via modulating AMPK-SIRT1-PGC1a energy metabolism pathway.

A large number of data suggest that caloric restriction (CR) has a protective effect on myocardial ischemia/reperfusion injury (I/R) in the elderly. However, the mechanism is still unclear. In this study, we created the I/R model in vivo by ligating the mice left coronary artery for 45 min followed by reperfusion. C57BL/6J wild-type mice were randomly divided into a young group fed ad libitum (y-AL), aged fed ad libitum (a-AL) and aged calorie restriction group (a-CR, 70% diet restriction), and fed for 6 weeks. The area of myocardial infarction was measured by Evan's blue-TTC staining, plasma cholesterol content quantified by ELISA, fatty acids and glucose measured by Langendorff working system, as well as protein expression of AMPK/SIRT1/PGC1a signaling pathway related factors in myocardial tissue detected by immunoblotting. Our results showed that CR significantly reduced infarct size in elderly mice after I/R injury, promoted glycolysis regardless of I/R injury, and restored myocardial glucose uptake in elderly mice. Compared with a-AL group, CR significantly promoted the expression of p-AMPK, SIRT1, p-PGC1a, and SOD2, but decreased PPARγ expression in aged mice. In conclusion, our results suggest that CR protects elderly mice from I/R injury by altering myocardial substrate energy metabolism via the AMPK/SIRT1/PGC1a pathway.

Arsenic-fluoride co-exposure induced endoplasmic reticulum stress resulting in apoptosis in rat heart and H9c2 cells.

Exposure to arsenic (As) or fluoride (F) has been shown to cause cardiovascular disease (CVDs). However, evidence about the effects of co-exposure to As and F on myocardium and their mechanisms remain scarce. Our aim was to fill the gap by establishing rat and H9c2 cell exposure models. We determined the effects of As and/or F exposure on the survival rate, apoptosis rate, morphology and ultrastructure of H9c2 cells; in addition, we tested the related genes and proteins of endoplasmic reticulum stress (ERS) and apoptosis in H9c2 cells and rat heart tissues. The results showed that As and/or F exposure induced early apoptosis of H9c2 cells and caused endoplasmic reticulum expansion. Additionally, the mRNA and protein expression levels of GRP78, PERK and CHOP in H9c2 cells were higher in the exposure groups than in the control group, and could be inhibited by 4-PBA. Furthermore, we found that As and/or F exposure increased the expression level of GRP78 in rat heart tissues, but interestingly, the expression level of CHOP protein was increased in the F and As groups, while significantly decreased in the co-exposure group. Overall, our results suggested that ERS-induced apoptosis was involved in the damage of myocardium by As and/or F exposure. In addition, factorial analysis results showed that As and F mainly play antagonistic roles in inducing myocardial injury, initiating ERS and apoptosis after exposure.