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

Abstract

BackgroundLong term low-dose benzene exposure leads to the inhibition of haematopoiesis. However, the underlying mechanisms remained poorly defined, especially mediated by early effector molecules.MethodsHere, 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.FindingsExposure to benzene can trigger pyroptosis via TET2 directly regulating the Aim2/Casp1 signaling pathway to cause haematotoxicity.InterpretationBenzene 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.FundNational 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.

Plasma metabolomics study reveals the critical metabolic signatures for benzene-induced hematotoxicity

“…Recent epidemiological studies have shown that global acute myelocytic leukemia (AML) morbidity and mortality have been increasing over the past 28 years and that occupational exposure to benzene is considered a major risk factor ( 1 ). According to the latest report from the National Bureau of Statistics, China’s pure benzene output has been increasing year after year, which may partly explain why the benzene poisoning and leukemia cases have remained high in recent years ( 2 ). Previous studies have shown that workers exposed to 1 ppm benzene exhibited no substantial WBC harm, but their BM hematopoietic capability was severely reduced in terms of renewal and differentiation ( 3 ).…”

The shape of low-concentration dose–response functions for benzene: implications for human health risk assessment

“…It has recently been discovered that inflammation mediated by a specific intracellular signaling platform (the NLRP3 inflammasome) that self-assembles in the cytosol of immune cells in response to exposures above an activation threshold (Cox 2019) drives the pathogenesis of MDS (Sallman and List 2019). Recent findings that benzene induces inflammatory programmed cell death (pyroptosis) (Sallman et al 2016;Guo et al 2019) and autophagy (Qian et al 2019) underscore the importance of inflammatory responses in benzene-induced pathogenesis. Although inflammation increases ROS and oxidative stress and cell turnover, thus potentially increasing formation and proliferation of HSCs with unrepaired cytogenetic damage and chromosomal aberrations, the inflammatory MoA suggests that it is the underlying inflammation that drives health risks.…”

Ciência, Tecnologia E Inovação: Do Campo À Mesa

“…Listadas na Tabela 1 (OSÓRIO, 2018). desenvolver anestesia do sistema nervoso central e falência de órgãos, enquanto as exposições a longo prazo em baixas doses causam diminuição na contagem de células sanguíneas periféricas, envenenamento crônico por benzeno e até neoplasias hematológicas como SMD e leucemia, além de mutações cromossômicas (GUO et al, 2019). [300] A biorremediação é um processo que utiliza principalmente microrganismos, plantas, enzimas microbianas ou vegetais para desintoxicar e degradar contaminantes no solo e em outros ambientes, com a finalidade de restaurar a saúde do ecossistema (GOUMA et al, 2014).…”