Effects of heavy metals on cardiovascular diseases in pre and post-menopausal women: from big data to molecular mechanism involved

To assess the link between a mixed heavy metal (cadmium, lead, and mercury) and the 10-year risk of cardiovascular diseases (CVDs) in pre- and post-menopausal Korean women aged ≥20 years, as well as identify potential molecular mechanisms of mixed heavy metal-induced CVDs. Multivariate linear regression, weighted quantile sum (WQS) regression, quantile g-computation (gqcomp), and Bayesian kernel machine regression (BKMR) models were used to examine the effects of mixed heavy metals and the 10-year risk of CVDs. The Comparative Toxicogenomics Database, MicroRNA ENrichment TURned NETwork, and the microRNA sponge generator and tester were used as the key data-mining approaches. In our BKMR analysis, we found that the overall effect of mixed heavy metals was linked to the 10-year risk of CVDs in postmenopausal women in the upper 20th percentiles and in premenopausal women in the upper 55th percentiles. Mercury was identified as the key chemical for the 10-year risk of CVDs in pre- and postmenopausal women. In silico analysis revealed that a heavy metal mixture interacted with six genes associated with CVD development. Physical interactions (77.6%) were found to be the most common among CVD-related genes induced by the heavy metals studied. Several pathways have been identified as the main molecular mechanisms that could be affected by studied heavy metals and are implicated in the development of CVDs (e.g., lipid and lipoprotein metabolism, lipoprotein metabolism, cholesterol metabolism, and cardiovascular disease). ALB, APOE, ATF5, and CREB3L3 were the key genes and transcription factors related to CVDs induced by the mixture of the investigated heavy metals, respectively. The two miRNAs with the highest interaction and expression in the development of CVDs were hsa-miR-199a-5p and hsa-miR-199a-3p. We also designed and tested miRNA sponge sequences for these miRNAs. The cutoff thresholds for each heavy metal level linked with the 10-year risk of CVDs were described. A mixture of heavy metal exposures, especially mercury, was more strongly linked with the 10-year risk of CVDs in postmenopausal women than in premenopausal women. Early interventions in postmenopausal women should be considered to reduce CVD risks.