Identification of Breast-Cancer-Associated Properties of Drinking Water under a Composite-Toxicity Perspective of Mixed Contaminants: A Case Study in a High-Prevalence Area of China

Breast cancer is the most frequently diagnosed female cancer worldwide. Environmental contaminant exposure is suspected to be crucial, but the broad-spectrum communal properties that these suspected contaminants all share remain to be explored, especially in source and drinking water. In this work, we focused on the Pearl River Basin, which has the highest breast cancer incidence and mortality in China, and hypothesized that the breast cancer risk in this area is associated with its water source. Our objective was to resolve the possible communal properties that are associated with breast cancer from water mixture extracts of source and drinking water and to identify the key drivers by utilizing the latest epidemiology data, performing an exhaustive water toxicological and chemical characterization, and combining partial least-squares path statistics modeling (PLS-PM). We proposed a path for a drinking water-toxicity-induced breast cancer risk and confirmed its association with estrogen-receptor- and thiol-depletion-relevant mechanisms. The breast cancer incidence risk was associated with water-mixture-promoted mammalian cell proliferation (i.e., estrogenic effect), while the mortality risk was associated with a greater thiol depletion (i.e., oxidative stress). Endocrine-disrupting chemicals (EDCs) and dissolved organic matter (DOM) from anthropogenic sources in drinking water are key drivers for estrogenic effects and oxidative stress, respectively. The PLS-PM standardized effects of the DOM and EDCs in treated water on the breast cancer incidence and mortality were &minus:0.07 and 0.31, and 0.35 and 0.31, respectively, further revealing that EDCs strongly influence the incidence risk, whereas the mortality risk resulted from the joint effects of EDCs and DOM. This study clearly shows an association between the breast cancer risk and drinking water toxicity in a high-prevalence area of China, broadening the future perspectives for water-contaminant-specific breast cancer prevention research.