Identification of Lipidomic Biomarkers for Coexposure to Subtoxic Doses of Benzo[a]pyrene and Cadmium: The Toxicological Cascade Biomarker Approach

Abstract

The search for model bioassay systems indicating activation of different toxicological signaling pathways is one of the paramount goals of modern toxicology. Especially coexposure scenarios need to be investigated with respect to synergistic and interdependent effects for the activation of toxicological signaling pathways. The present study introduces an experimental in vitro model system for nontoxic and low-dose coexposures of human mammary carcinoma MCF-7 cells against polycyclic aromatic hydrocarbons (PAHs) such as benzo[a]pyrene (BP) and heavy metals such as cadmium. For the first time, a multivariate model that identifies 18 metabolic biomarkers has been shown to be sufficient to separate BP-treated cells from coexposed 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 that could be used to identify profiles associated with tumorigenic potency of environmental toxicants in coexposure scenarios, including possible synergistic or additive effects.

Pilot Metabolome-Wide Association Study of Benzo(a)pyrene in Serum From Military Personnel

“…This trend was not observed in the present study. Lipid profiling of human mammary cells dosed with BaP also identified alterations in sphingomyelins and glycerophospholipids (50), which was determined to be receptor independent and metabolically associated. BaP was also shown to alter cholesterol-rich micro domains, resulting in changed fatty acid composition and reduced cholesterol in rat liver epithelial cells.…”

Differential cellular metabolite alterations in HaCaT cells caused by exposure to the aryl hydrocarbon receptor-binding polycyclic aromatic hydrocarbons chrysene, benzo[ a ]pyrene and dibenzo[ a,l ]pyrene

“…, AHR, p53 or Nrf2) resulting metabolomic marker sets could be related to those pathway steps. This way metabolomic biomarkers indicative for inhibition or activation of relevant signaling pathways could be identified [35] . All this information would finally help to develop in vitro risk assessment strategies for PAH mixtures.…”

“…Processing of metabolomics data was carried out using the statistical package SPSS + (version 12.0.2G) as described elsewhere [35] . In brief, each sample was standardized to the mean of the control (set to 100%) and normalized using z-score values.…”

Alterations in eicosanoid composition during embryonic development in the chorioallantoic membrane of the American alligator (Alligator mississippiensis) and domestic chicken (Gallus gallus)

“…While this trend has gained traction in the biomedical sciences community, it has recently surged in the environmental monitoring and comparative endocrinology arena (Garcia-Reyero et al, 2014; Jungnickel et al, 2014; Scanlan et al, 2015; Schneider and Orchard, 2011). In this study, we created a new ‘eicosanomic’ strategy for the quantitation of the eicosanoid milieu in non-traditional species, models, and/or matrices.…”