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Effects of chlorpyrifos and trichloropyridinol on HEK 293 human embryonic kidney cells
VanEmon, J., P. Pan, AND F. Van Breukelen. Effects of chlorpyrifos and trichloropyridinol on HEK 293 human embryonic kidney cells. CHEMOSPHERE. Elsevier Science Ltd, New York, NY, 191:537-547, (2018).
Toxicological risk assessments have traditionally focused on apical endpoints rather than the biologic changes leading to an adverse health outcome. These studies can be expensive, rely heavily on animals and require species extrapolation for human health risk assessment (NRC, 2007). The traditional toxicological approach of relying solely on whole animal testing to assess the effects of xenobiotics on human and ecological health cannot keep pace with the thousands of chemicals already in existence or the new chemicals constantly being introduced. The National Academy of Sciences report, Toxicity Testing in the 21st Century laid the foundation for a paradigm shift toward the use of other scientific tools to expand in vitro pathway-based toxicity testing and minimize whole animal approaches (NRC, 2007). These alternative methods such as bioinformatics analyses of exposed human cell cultures are gaining acceptance at predicting in vivo toxicity using a bottom-up-approach (Adeleye et al., 2015; Grafstrom et al., 2015; Rouquie et al, 2015) and helping in adverse outcome pathway (AOP) development (Ankley et al., 2010; OECD, 2013; Groh et al., 2015).
Chlorpyrifos (CPF) [O, O-diethyl -O-3, 5, 6-trichloro-2-pyridyl phosphorothioate] is an organophosphate insecticide widely used for agricultural and urban pest control. Trichloropyridinol (TCP; 3,5,6-trichloro-2-pyridinol), the primary metabolite of CPF, is often used as a generic biomarker of exposure for CPF and related compounds. Human embryonic kidney 293 (HEK 293) cells were exposed to CPF and TCP with varying concentrations and exposure periods. Cell cultures enable the cost-effective study of specific biomarkers to help determine toxicity pathways to predict the effects of chemical exposures without relying on whole animals. Both CPF and TCP were found to induce cytotoxic effects with CPF being more toxic than TCP with EC50 values of 68.82 μg/mL and 146.87 μg·ml−1 respectively. Cell flow cytometric analyses revealed that exposure to either CPF or TCP leads to an initial burst of apoptotic induction followed by a slow recruitment of cells leading towards further apoptosis. CPF produced a strong induction of IL6, while TCP exposure resulted in a strong induction of IL1α. Importantly, the concentrations of CPF and TCP required for these cytokine inductions were higher than those required to induce apoptosis. These data suggest CPF and TCP are cytotoxic to HEK 293 cells but that the mechanism may not be related to an inflammatory response. CPF and TCP also varied in their effects on the HEK 293 proteome with 5 unique proteins detected after exposure to CPF and 31 unique proteins after TCP exposure.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL EXPOSURE RESEARCH LABORATORY
EXPOSURE METHODS & MEASUREMENT DIVISION