Abstract
ObjectiveThe objective of this study is to characterize key pathways that contribute to the hepatotoxic effects of two dipyridyl herbicides, paraquat and diquat.MethodsDose‐dependent toxicity assays were performed in an in vitro liver model (TGF‐alpha transgenic mouse hepatocytes; TAMH) to determine LC50 values for paraquat and diquat. Transient knockdown of JNK and p53 was performed using siRNA. Target knockdowns were confirmed using protein immunoblotting. Cell viability assays were then conducted to determine how each transfection affected cell survival following exposure to either paraquat or diquat.ResultsLC50 values were determined to be 57μM and 18μM for paraquat and diquat, respectively. siRNA‐based knockdown decreased JNK protein expression by 31%. This correlated with significant increases in cell viability for transfected cells exposed to either paraquat (21%) or diquat (15%). siRNA‐based knockdown decreased p53 protein expression by 66%. This correlated with a significant but small decrease in the viability of transfected cells exposed to paraquat only (6%).ConclusionExperimental LC50 values revealed diquat to be more hepatotoxic than paraquat in the TAMH line. The siRNA‐based knockdown of JNK provides evidence that JNK plays a crucial role in propagating toxicity caused by these herbicides. In contrast, effects from the p53 knockdown experiments had either no effect (diquat exposure) or propagated toxicity to a small but significant extent (paraquat). These observations suggest affecting targets that precede p53 during apoptotic signaling are crucial to rescuing hepatocytes from the toxic effects of dipyridyl herbicides.Support or Funding InformationThis work was supported by the Pacific University Research Incentive Grant Program and an ASPET Summer Undergraduate Research Fellow (SURF) Individual Award.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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