Benzene-induced mouse hematotoxicity is regulated by a protein phosphatase 2A complex that stimulates transcription of cytochrome P4502E1

Abstract

Edited by Joel M. GottesfeldChronic benzene exposure is associated with hematotoxicity and the development of aplastic anemia and leukemia. However, the signaling pathways underlying benzene-induced hematotoxicity remain to be defined. Here, we investigated the role of protein phosphatase 2A (PP2A) in the regulation of benzeneinduced hematotoxicity in a murine model. Male mice with a hepatocyte-specific homozygous deletion of the Ppp2r1a gene (encoding PP2A A␣ subunit) (HO) and matched wildtype (WT) mice were exposed to benzene via inhalation at doses of 1, 10, and 100 ppm for 28 days. Peripheral white blood cell counts and activation of bone marrow progenitors were attenuated in the HO mice, indicating that Ppp2r1a deletion protects against benzene-induced hematotoxicity. Moreover, elevation of urinary S-phenyl mercapturic acid, a benzene metabolite, was much greater in WT mice than in HO mice. Real-time exhalation analysis revealed more exhaled benzene but fewer benzene metabolites in HO mice than in WT mice, possibly because of the down-regulation of Cyp2e1, encoding cytochrome P4502E1, in hepatocytes of the HO mice. Loss-of-function screening disclosed that PP2A complexes containing the B56␣ subunit participate in regulating Cyp2e1 expression. Notably, PP2A-B56␣ suppressioninHepG2cellsresultedinpersistent␤-cateninphosphorylation at Ser 33 -Ser 37 -Thr 41 in response to CYP2E1 agonists. In parallel, nuclear translocation of ␤-catenin was inhibited, concomitant with a remarkable decrease of Cyp2e1 expression. These findings support the notion that a regulatory cascade comprising PP2A-B56␣, ␤-catenin, and Cyp2e1 is involved in benzene-induced hematotoxicity, providing critical insight into the role of PP2A in responses to the environmental chemicals.

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

“…These results indicated that the benzene-exposed workers in this study were at low levels of benzene exposure and suffered no significant hematotoxicity. Whereas urinary SPMA was a sensitive biomarker reflecting low levels of benzene exposure, similar results were also found in both animals or populations from previous low-level benzene toxicity studies ( 25 , 26 ). An epidemiological study confirmed that, at airborne benzene concentrations < 1 ppm, the WBC counts of benzene-exposed workers were within the normal range (4 × 10 9 /L to 10 × 10 9 /L) for clinical diagnosis, but their renewal and differentiation of hematopoietic stem cells (HSCs) had been significantly restrained ( 3 ).…”

T-Cell-Specific CerS4 Depletion Prolonged Inflammation and Enhanced Tumor Burden in the AOM/DSS-Induced CAC Model

“…It has been shown that Cer d18:1/18:0 influences protein phosphatase 2A (PP2A) activity [27]. PP2A is involved in the transcriptional regulation of CYP2E1 and might contribute to the liver toxicity of AOM [28]. The transforming growth factor β (TGFβ) signaling pathway has also been shown to be involved in AOM-related liver toxicity [29].…”

Neuronal network remodeling and Wnt pathway dysregulation in the intra-hippocampal kainate mouse model of temporal lobe epilepsy

“…Similarly, our data also do not rule out Wnt-mediated control of neurogenesis via alternate downstream Wnt signaling pathways, such as the calcium or planar cell polarity pathways, or Wnt-mediated effects on circuit function that do not involve neurogenesis. Finally, although XAV939 has been shown to be selective for the Wnt pathway and to not affect the CRE (cAMP response element), NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells), or TGFb (transforming growth factor beta) pathways in reporter lines [25], and was effective in both in vivo and in vitro assays involving mice and neural cell types at the same dose used in this study [37–39], unexpected off-target drug effects must still be considered.…”

“…XAV939 (Millipore Sigma) was dissolved in filter-sterilized 10% DMSO / 45% saline / 45% poly-ethylene glycol-400 (Affymetrix) at a final concentration of 1mg/ml. Animals received intraperitoneal injections daily for 14 days with vehicle or XAV939 (5 mg/kg) after recovery from surgery, as this dose effectively inhibits beta-catenin signaling in translational models [37–39].…”