Independent and combined associations of urinary metals exposure with markers of liver injury: Results from the NHANES 2013-2016.

BACKGROUND: Heavy metals entering the human body could cause damage to a variety of organs. However, the combined harmful effects of exposure to various metals on liver function are not well understood. The purpose of the study was to investigate the independent and joint relationships between heavy metal exposure and liver function in adults. METHODS: The study involved 3589 adults from the National Health and Nutrition Examination Survey. Concentrations of urinary metals, including arsenic (As), cadmium (Cd), lead (Pb), antimony (Sb), barium (Ba), thallium (Tl), tungsten (W), uranium (U), were determined in urine using inductively coupled plasma mass spectrometry. Data for liver function biomarkers included alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transaminase (GGT), and alkaline phosphatase (ALP). Survey-weighted linear regression and quantile g-computation (qgcomp) were employed to evaluate the relationship of urinary metals with the markers of liver injury. RESULTS: Cd, U and Ba were found to have positive correlations with ALT, AST, GGT, and ALP in the survey-weighted linear regression analyses. According to the qgcomp analyses, the total metal mixture was positively correlated with ALT (percent change: 8.15; 95% CI: 3.84, 12.64), AST (percent change: 5.55; 95% CI: 2.39, 8.82), GGT (percent change: 14.30; 95% CI: 7.81, 21.18), and ALP (percent change: 5.59; 95% CI: 2.65, 8.62), and Cd, U, and Ba were the main contributors to the combined effects. Positive joint effects were observed between Cd and U on ALT, AST, GGT and ALP, and U and Ba had positive joint effects on ALT, AST and GGT. CONCLUSION: Exposures to Cd, U, and Ba were individually associated with multiple markers of liver injury. Mixed metal exposure might be adversely correlated with markers of liver function. The findings indicated the potential harmful effect of metal exposure on liver function.

Microcystins Exposure Associated with Blood Lipid Profiles and Dyslipidemia: A Cross-Sectional Study in Hunan Province, China.

Increasing evidence from experimental research suggests that exposure to microcystins (MCs) may induce lipid metabolism disorder. However, population-based epidemiological studies of the association between MCs exposure and the risk of dyslipidemia are lacking. Therefore, we conducted a population-based cross-sectional study involving 720 participants in Hunan Province, China, and evaluated the effects of MCs on blood lipids. After adjusting the lipid related metals, we used binary logistic regression and multiple linear regression models to examine the associations among serum MCs concentration, the risk of dyslipidemia and blood lipids (triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C)). Moreover, the additive model was used to explore the interaction effects on dyslipidemia between MCs and metals. Compared to the lowest quartile of MCs exposure, the risk of dyslipidemia [odds ratios (OR) = 2.27, 95% confidence interval (CI): 1.46, 3.53] and hyperTG (OR = 3.01, 95% CI: 1.79, 5.05) in the highest quartile was significantly increased, and showed dose-response relationships. MCs were positively associated with TG level (percent change, 9.43%; 95% CI: 3.53%, 15.67%) and negatively associated with HDL-C level (percent change, -3.53%; 95% CI: -5.70%, -2.10%). In addition, an additive antagonistic effect of MCs and Zn on dyslipidemia was also reported [relative excess risk due to interaction (RERI) = -1.81 (95% CI: -3.56, -0.05)], and the attributable proportion of the reduced risk of dyslipidemia due to the antagonism of these two exposures was 83% (95% CI: -1.66, -0.005). Our study first indicated that MCs exposure is an independent risk factor for dyslipidemia in a dose-response manner.

Combination Effect of Microcystins and Arsenic Exposures on CKD: A Case-Control Study in China.

Evidence has shown that exposure to environmental pollutants such as microcystins (MCs), arsenic (As), and cadmium (Cd) can lead to the occurrence and development of chronic kidney disease (CKD). There is a synergistic effect between MCs and Cd. However, the combined effect of MCs and As exposures on CKD remains unclear. In Hunan province, China, 135 controls and 135 CKD cases were enrolled in a case-control study. Serum MCs, plasma As and Cd concentrations were measured for all participants. We investigated the association between MCs/As and CKD risk using conditional logistic regression. The additive model explored the interaction effect, and the Bayesian kernel machine regression (BKMR) models investigated the combined effects of MCs, As, and Cd on CKD. The results showed that MCs and As were significantly associated with CKD risk. Participants in the highest MCs concentration had a 4,81-fold increased risk of CKD compared to those in the lowest quartile (95% confidence interval [CI]: 1,96 to 11,81). The highest quartile of As concentrations corresponded to an adjusted odds ratio of 3.40 (95% CI: 1.51, 7.65) relative to the lowest quartile. MCs/As and CKD risk exhibited significant dose-response correlations (all p for trend < 0.01). In addition, a positive interaction effect of MCs and As on CKD was also reported. The CKD risk due to interaction was 2.34 times (95% CI: 0.14, 4.54) relative to the CKD risk without interaction, and the attributable proportion of CKD due to interaction among individuals with both exposures was 56% (95% CI: 0.22, 0.91). In the BKMR, the combined effect of MCs, As, and Cd was positively associated with CKD. In conclusion, both MCs and As are independent risk factors for CKD, exerting a synergistic effect between them. Combined exposure to MCs, As, and Cd can increase the risk of CKD.

Microcystin-LR Combined with Cadmium Exposures and the Risk of Chronic Kidney Disease: A Case-Control Study in Central China.

Increasing evidence indicates that exposure to microcystin-LR (MC-LR) can cause kidney damage. However, the association between MC-LR exposure and chronic kidney disease (CKD) risk in humans has not been studied. Therefore, we conducted a population-based case-control study involving 135 CKD cases and 135 matched controls in central China and analyzed the effects of MC-LR alone as well as combined with the known risk factor cadmium (Cd). Compared to the lowest quartile of MC-LR exposure, the highest quartile had a 6.56-fold (95% confidence interval [CI]: 2.46, 17.51) significantly increased risk for CKD, displaying a dose-response relationship (ptrend < 0.001). Our animal study also showed that MC-LR exposure induced kidney injury via the PI3K/AKT/mTOR signaling pathway. Comparing the highest Cd quartile to the lowest, the adjusted odds ratio for CKD was 3.88 (95% CI: 1.47, 10.28), exhibiting a dose-response relationship (ptrend < 0.006). Furthermore, a positive additive interaction was observed between MC-LR and Cd (relative excess risk due to interaction = 1.81, 95% CI: 0.42, 3.20; attributable proportion of interaction = 0.70, 95% CI: 0.35, 1.05). Our study firstly revealed that MC-LR exposure is an independent risk factor for CKD and has a synergistic relationship with Cd. MC-LR and Cd exposures are associated with CKD risk in a dose-response manner.

Long-term environmental levels of microcystin-LR exposure induces colorectal chronic inflammation, fibrosis and barrier disruption via CSF1R/Rap1b signaling pathway.

Microcystin-LR (MC-LR) is a very common toxic cyanotoxins threating ecosystems and the public health. This study aims to explore the long-term effects and potential toxicity mechanisms of MC-LR exposure at environmental levels on colorectal injury. We performed histopathological, biochemical indicator and multi-omics analyses in mice with low-dose MC-LR exposure for 12 months. Long-term environmental levels of MC-LR exposure caused epithelial barrier disruption, inflammatory cell infiltration and an increase of collagen fibers in mouse colorectum. Integrated proteotranscriptomics revealed differential expression of genes/proteins, including CSF1R, which were mainly involved in oxidative stress-induced premature senescence and inflammatory response. MC-LR induced chronic inflammation and fibrosis through oxidative stress and CSF1R/Rap1b signaling pathway were confirmed in cell models. We found for the first time that long-term environmental levels of MC-LR exposure caused colorectal chronic inflammation, fibrosis and barrier disruption via a novel CSF1R/Rap1b signaling pathway. Moreover, MC-LR changed the gut microbiota and microbial-related metabolites in a vicious cycle aggravating colorectal injury. These findings provide novel insights into the effects and toxic mechanisms of MC-LR and suggest strategies for the prevention and treatment of MC-caused intestinal diseases.