Benzene metabolites trigger pyroptosis and contribute to haematotoxicity via TET2 directly regulating the Aim2/Casp1 pathway

BACKGROUND: Long term low-dose benzene exposure leads to the inhibition of haematopoiesis. However, the underlying mechanisms remained poorly defined, especially mediated by early effector molecules. METHODS: Here, we first found in mRNA microarray that pyroptotic classic genes (Casp1, 4, 5, and IL1β) were up-regulated and represented dose-dependent differential expression in controls, low-dose benzene-exposed and chronic benzene-poisoned workers, and the expression of Casp1 and IL1β were confirmed in low-dose benzene-exposed workers and was accompanied with elevated potent proinflammatory IL1β. In vitro studies showed that benzene metabolites induced AHH-1 cell pyroptosis through activating Aim2/Casp1 pathway with the increased expression of GSDMD. Meanwhile, TET2 overexpression was elevated in vivo and in vitro and it was positively correlated with IL1β. Further, we verified that pyroptosis caused by 1,4-BQ could be ameliorated in vitro by RNAi or pretreatment with Dimethyloxalylglycine (DMOG), the inhibitor of TET2. FINDINGS: Exposure to benzene can trigger pyroptosis via TET2 directly regulating the Aim2/Casp1 signaling pathway to cause haematotoxicity. INTERPRETATION: Benzene metabolites induced pyroptotic cell death through activation of the Aim2/Casp1 pathway which can be regulated by Tet2 overexpression. Tet2 may be a potential risk factor and is implicated in the development of benzene-related diseases. FUND: National Natural Science Foundation of China; the Support Project of High–level Teachers in Beijing Municipal Universities in the Period of 13th Five–year Plan; Beijing Natural Science Foundation Program and Scientific Research Key Program of Beijing Municipal Commission of Education.