Cadmium exposure is associated with colorectal neoplasm risk: From epidemiological evidence to laboratory confirmation.

Cadmium (Cd) is a well-established carcinogenic heavy metal linked to the development of various cancers. However, its role in colorectal neoplasms remains unclear. Using a cross-sectional design involving 2332 Chinese participants, we examined the association between Cd exposure and colorectal neoplasms and further explored underlying mechanisms using murine models exposed to environmentally relevant Cd concentrations in drinking water. Epidemiological analysis showed that elevated whole-blood Cd levels were associated with an increased risk of both non-advanced (prevalence ratio [PR] per log2-transformed increment = 1.12, 95% confidence interval [CI]: 1.05-1.20) and advanced colorectal neoplasms (PR per log2-transformed increment = 1.18, 95% CI: 1.01-1.37). In mice, although Cd exposure did not adversely affect overall health status or intestinal structure, it significantly promoted tumorigenesis and malignant progression in the azoxymethane/dextran sulfate sodium (AOM/DSS) model. Notably, Cd exposure did not affect tumor development in the AOM-only model, suggesting that its tumor-promoting effect is dependent on concurrent intestinal inflammation. Indeed, Cd exposure exacerbated DSS-induced colitis in mice. Additionally, Cd exposure induced distinct gut microbiota alterations, characterized by depletion of Lactobacillus intestinalis, as well as members of Turicibacter and Gordonibacter, and enrichment of members of Enterorhabdus, Allobaculum, and Atopobiaceae. Collectively, findings from both the epidemiological cohort and murine models suggest a significant link between Cd exposure and colorectal neoplasms. Moreover, these data reveal the critical roles of inflammation and gut microbiota alterations in Cd-promoted colorectal tumorigenesis.