Trace metal exposure and hypertension risk: A systematic review and meta-analysis

This study systematically evaluates the association between trace metal exposure and hypertension risk, explores dose-response patterns, and investigates underlying molecular mechanisms. A systematic review was conducted according to PRISMA guidelines, including 39 high-quality observational studies retrieved from PubMed, Web of Science, Embase, and the Cochrane Library. Meta-analysis results showed a significant positive association between blood lead exposure and hypertension (OR = 1.16, 95% CI: 1.02-1.31) as well as gestational hypertension (OR = 1.56, 95% CI: 1.21-2.02). Conversely, blood manganese demonstrated a potential protective effect, showing a monotonically declining linear trend with hypertension risk and a significantly reduced risk of gestational hypertension (OR = 0.40, 95% CI: 0.25-0.65). Dose-response analysis based on restricted cubic splines revealed nonlinear patterns: blood cadmium exhibited a U-shaped dose-response relationship (P non-linear = 0.005) with risk rising markedly above 3.5 µg/L, and dietary zinc showed a J-shaped curve (P non-linear = 0.004) peaking around 22 mg/day. Urinary biomarkers (cadmium, lead, arsenic, zinc, vanadium, and cobalt) generally showed stronger associations with hypertension than blood biomarkers. However, for several metals - including vanadium, cobalt, chromium, and nickel - the available evidence was limited to one to three studies, and the corresponding risk estimates should therefore be interpreted with caution and require confirmation in future larger-scale studies. Bioinformatics analysis highlighted that trace metal exposure may promote hypertension through mechanisms such as oxidative stress, inflammatory responses (e.g., TNF signaling), and disruption of the AGE-RAGE pathway. The findings suggest that lead exhibits threshold-free linear toxicity, while manganese may have a protective effect. Pregnant women were identified as a particularly sensitive population to environmental metal exposure. This study provides epidemiological evidence and explores molecular mechanisms, supporting preventive strategies for environmentally induced hypertension. The image summary is shown in the Graphical Abstract.