Molecular mechanisms of heavy metal-induced cancer: Insights from animal models and human implications
TL;DR
Evaluation of the role of gut microbiome interactions in modulating metal bioavailability and carcinogenic potential, limitations of traditional animal models for mixture risk assessment, and emerging technologies, including single-cell sequencing, CRISPR-based functional genomics, and organ-on-chip platforms that may resolve current knowledge gaps are included.
Abstract
Heavy metals and metalloids, including arsenic (As), cadmium (Cd), chromium (Cr), nickel (Ni), lead (Pb), and mercury (Hg), are well-recognised human carcinogens, and the molecular mechanisms underlying their carcinogenicity are incompletely characterised. In this review, we critically discuss and synthesise the available evidence on how heavy metals and metalloids contribute to cancer development by inducing ROS, oxidative stress, DNA damage, mitochondrial dysfunction, endoplasmic reticulum stress, and alterations in apoptotic regulators such as p53, Bax, and Bcl-2. Metal-specific differences in genotoxic versus cytotoxic mechanisms and assessing endogenous protective responses, including metallothionein sequestration, antioxidant pathways, and chelation, are included. An extended analysis of the toxicodynamics of metal mixtures is also made, focusing on a realistic but underexplored exposure scenario. Co-occurring metal combinations, such as As-Cd-Cr-Pb, produce endpoint-specific interaction profiles that pose a greater risk for neurological and genotoxic effects than for renal endpoints and cardiovascular effects, depending on the binary combination. Cd and As co-exposure produces synergistic DNA damage 3–5 times greater than predicted from single-metal effects through concurrent p53 dysfunction and ROS overload. Evaluation of the role of gut microbiome interactions in modulating metal bioavailability and carcinogenic potential, limitations of traditional animal models for mixture risk assessment, and emerging technologies, including single-cell sequencing, CRISPR-based functional genomics, and organ-on-chip platforms that may resolve current knowledge gaps, are included.