Identification of lipidomic biomarkers for coexposure to subtoxic doses of benzo[a]pyrene and cadmium: The toxicological cascade biomarker approach

The search for model bioassay systems indicating activation of different toxicological signaling pathways is one of the paramount goals of modern toxicology. Especially co-exposure scenarios need to be investigated in respect to synergistic and interdependent effects for the activation of toxicological signaling pathways. The present study introduces an experimental in vitro model system for non-toxic and low-dose co-exposures of human mammary carcinoma MCF-7 cells against polycyclic aromatic hydrocarbons (PAHs; e.g., benzo[a]pyrene, BP) and heavy metals (e.g., cadmium, Cd). For the first time, a multivariate model identifies 18 metabolic biomarkers being sufficient to separate BP-treated cells from co-exposed or control cells. A “toxicological pathway color code model” is introduced to visualize the results. Different biomarker subsets can be associated with specific HER2 signaling steps. A tiered cascade biomarker approach is proposed, which could be used to identify profiles associated with tumorigenic potency of environmental toxicants in co-exposure scenarios including possible synergistic or additive effects.