Circular RNA circRest regulates manganese induced cell apoptosis by targeting the mmu-miR-6914-5p/Ephb3 axis.

Overexposure to manganese (Mn) can lead to neurotoxicity, the underlying mechanisms remain incompletely understood. Circular RNAs (circRNAs) have emerged as important regulators in various biological processes. It is plausible that circRNAs may be involved in the biological mechanisms underlying Mn caused neurotoxicity. Here, circRest was downregulated in Mn-exposed mouse neuroblastoma cells (N2a cells) by RNA sequencing and quantitative real-time PCR. When circRest was overexpressed, it led to an increase in cell viability and a decrease in apoptosis following Mn exposure. Conversely, silencing circRest resulted in opposite effects in N2a cells. Further investigation revealed that circRest acts as a mmu-miR-6914-5p sponge, and mmu-miR-6914-5p could bind and inhibit Ephb3, thereby promoting apoptosis in N2a cells. This was confirmed through RNA antisense purification and dual luciferase reporter assays. Additionally, the circRest/mmu-miR-6914-5p/Ephb3 axis may influence memory and learning in mice following Mn exposure. In conclusion, our study uncovers a novel mechanism by which circRest may attenuate Mn caused neurotoxicity via the mmu-miR-6914-5p/Ephb3 axis.

Metal mixture exposure and the risk for immunoglobulin A nephropathy: Evidence from weighted quantile sum regression.

Immunoglobulin A nephropathy (IgAN) is the most common type of glomerulonephritis in adults worldwide. Environmental metal exposure has been reported to be involved in the pathogenic mechanisms of kidney diseases, yet no further epidemiological study has been conducted to assess the effects of metal mixture exposure on IgAN risk. In this study, we conducted a matched case‒control design with three controls for each patient to investigate the association between metal mixture exposure and IgAN risk. A total of 160 IgAN patients and 480 healthy controls were matched for age and sex. Plasma levels of arsenic, lead, chromium, manganese, cobalt, copper, zinc, and vanadium were measured using inductively coupled plasma mass spectrometry. We used a conditional logistic regression model to assess the association between individual metals and IgAN risk, and a weighted quantile sum (WQS) regression model to analyze the effects of metal mixtures on IgAN risk. Restricted cubic splines were used to evaluate overall associations between plasma metal concentrations and estimated glomerular filtration rate (eGFR) levels. We observed that except for Cu, all the metals analyzed were nonlinearly associated with decreased eGFR, and higher concentrations of arsenic and lead were associated with elevated IgAN risk in both single-metal [3.29 (1.94, 5.57), 6.10 (3.39, 11.0), respectively] and multiple-metal [3.04 (1.66, 5.57), 4.70 (2.47, 8.97), respectively] models. Elevated manganese [1.76 (1.09, 2.83)] levels were associated with increased IgAN risk in the single-metal model. Copper was inversely related to IgAN risk in both single-metal [0.392 (0.238, 0.645)] and multiple-metal [0.357 (0.200, 0.638)] models. The WQS indices in both positive [2.04 (1.68, 2.47)] and negative [0.717 (0.603, 0.852)] directions were associated with IgAN risk. Lead, arsenic, and vanadium contributed significant weights (0.594, 0.195, and 0.191, respectively) in the positive direction; copper, cobalt, and chromium carried significant weights (0.538, 0.253, and 0.209, respectively). In conclusion, metal exposure was related to IgAN risk. Lead, arsenic, and copper were all significantly weighted factors of IgAN development, which may require further investigation.

Long noncoding RNA Sh2d3c promotes manganese-induced neuronal apoptosis through the mmu-miR-675-5p/Chmp4b/Bax axis.

Environmental excessive manganese (Mn) exposure can cause neurotoxicity and neurodegenerative diseases. Long noncoding RNAs (lncRNAs) have been shown to affect the development of neurodegenerative diseases. However, whether lncRNAs are also linked to Mn-induced neurotoxicity has not been reported. In this study, we explored the role of lncRNAs in Mn-induced neurotoxicity and its mechanisms. LncSh2d3c was identified to be the significantly increased lncRNA in Mn-exposed N2a cells. Knockdown of lncSh2d3c increased the cell viability and inhibited cell apoptosis. Mechanistically, lncSh2d3c acted as a sponge for mmu-miR-675-5p, thereby preventing the inhibitory effect of mmu-miR-675-5p on Chmp4b. The binding potency of lncSh2d3c/mmu-miR-675-5p and mmu-miR-675-5p/Chmp4b was verified by RNA antisense purification (RAP) and luciferase reporter assays. Furthermore, we also found that the lncSh2d3c/mmu-miR-675-5p/Chmp4b/Bax axis might be associated with the learning ability and memory of mice after Mn exposure. These results revealed a novel mechanism of Mn-induced neuronal apoptosis through the lncSh2d3c/mmu-miR-675-5p/Chmp4b/Bax axis and suggested that lncSh2d3c may act as a key regulatory factor in Mn-induced neurotoxicity.

Exposure to perfluoroalkyl substances in early pregnancy and the risk of hypertensive disorders of pregnancy: A nested case-control study in Guangxi, China.

BACKGROUND: Previous epidemiological studies have examined the associations between exposure to perfluoroalkyl substances (PFASs) and the risk of hypertensive disorders of pregnancy (HDP). However, these studies have drawn discrepant conclusions and have some limitations. METHODS: A nested case-control study was conducted with the Guangxi Zhuang Birth Cohort (GZBC), a prospective, ongoing birth cohort that was implemented in Guangxi, China, in June 2015. Maternal serum concentrations of nine PFASs were measured using ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS). The associations between PFAS exposure and the risk of HDP were assessed using logistic regression (single-exposure), weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR) models. RESULTS: A total of 136 HDP cases and 408 controls were enrolled in this study. In logistic regression models, perfluoroundecanoic acid (PFUnA), perfluorooctane sulfonate (PFOS), perfluorononanoic acid (PFNA) and perfluorobutanesulfonic acid (PFBS) were positively associated with HDP, while perfluorohexane sulfonate (PFHxS) was inversely associated with HDP. In the BKMR analysis, the joint effect of PFASs was positively associated with HDP. PFOS and PFBS showed positive trends, while PFHxS and PFHpA showed inverse trends. In WQS regression analysis, we calculated two WQS indices that were estimated using constraints in both the positive and negative directions of effects. Both WQS indices were significantly associated with HDP (OR: 2.663, 95% CI: 1.795-3.951; OR: 0.338, 95% CI: 0.229-0.499, respectively). PFBS, PFOS and PFUnA had significant weights in the positive effect direction; PFHxS, perfluoroheptanoic acid (PFHpA) and perfluorododecanoic acid (PFDoA) had significant weights in the negative effect direction. CONCLUSION: Considering all model results, we found that combined exposure to nine PFASs had a positive effect on the development of HDP. Moreover, PFOS and PFBS were positively associated with the HDP risk, while PFHxS and PFHpA were negatively associated with the HDP risk in women in Guangxi, China.