Benzene-Induced Hematopoietic Neoplasms Including Myeloid Leukemia in Trp53-Deficient C57BL/6 and C3H/He Mice

Abstract

This research focused on three major questions regarding benzene-induced hematopoietic neoplasms (HPNs). First, why are HPNs induced equivocally and at only threshold level with low-dose benzene exposure despite the significant genotoxicity of benzene even at low doses both in experiments and in epidemiology? Second, why is there no linear increase in incidence at high-dose exposure despite a lower acute toxicity (LD(50) > 1000 mg/kg body weight; WHO, 2003, Benzene in drinking-water. Background document for development of WHO Guidelines for Drinking-Water Quality)? Third, why are particular acute myeloid leukemias (AMLs) not commonly observed in mice, although AMLs are frequently observed in human cases of occupational exposure to benzene? In this study, we hypothesized that the threshold-like equivocal induction of HPNs at low-dose benzene exposure is based on DNA repair potential in wild-type mice and that the limited increase in HPNs at a high-dose exposure is due to excessive apoptosis in wild-type mice. To determine whether Trp53 deficiency satisfies the above hypotheses by eliminating or reducing DNA repair and by allowing cells to escape apoptosis, we evaluated the incidence of benzene-induced HPNs in Trp53-deficient C57BL/6 mice with specific regard to AMLs. We also used C3H/He mice, AML prone, with Trp53 deficiency to explore whether a higher incidence of AMLs on benzene exposure might explain the above human-murine differences. As a result, heterozygous Trp53-deficient mice of both strains showed a nonthreshold response of the incidence of HPNs at the lower dose, whereas both strains showed an increasing HPN incidence up to 100% with increasing benzene exposure dose, including AMLs, that developed 38% of heterozygous Trp53-deficient C3H/He mice compared to only 9% of wild-type mice exposed to the high dose. The detection of AMLs in heterozygous Trp53-deficient mice, even in the C57BL/6 strain, implies that benzene may be a potent inducer of AMLs also in mice with some strain differences.

TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome

“…Evidence for this hypothesis comes from several observations in mice and human disease: (1) mouse studies requiring biallelic TP53 inactivation and a concomitant "second hit" for myeloid leukemogenesis 38,39 demonstrated that p53 lost myeloid progenitors exhibit aberrant self-renewal, thereby promoting AML 40 ; (2) in high-risk MDS and/or AML evolving from a 5qϪ syndrome, the expansion of preexisting TP53 mutated subclones was observed 41,42 ; and (3) recently, next-generation sequencing of a therapy-related CK-AML genome identified several acquired genetic lesions and a heterozygous intragenic germline TP53 deletion, becoming homozygous in AML as a result of acquired UPD(17p), 43 a mechanism possibly underlying the sequential TP53 inactivation in patient 96 (supplemental Figure 1).…”

A retrospective cohort study of cause‐specific mortality and incidence of hematopoietic malignancies in Chinese benzene‐exposed workers

“…Molecular data provide evidence of genotoxicity of benzene metabolites on pluripotent bone marrow progenitor cells . Animal studies, including an investigation in Tp53 ‐deficient mice, demonstrate that benzene may cause lymphomas, while decades of experimental research provide strong evidence that benzene is associated with a broad array of different types of neoplasms. Postulated mechanisms for benzene‐related lymphomagenesis include induction of chromosome rearrangements and immunosuppression …”

Benzene Exposure Alters Expression of Enzymes Involved in Fatty Acid β-Oxidation in Male C3H/He Mice

“…benzene is equivalent to the inhalation protocol with 300 ppm [19]. It is reported that a dose of 300 ppm benzene inhalation induced 9% acute myeloid leukemias (AMLs) in wild-type C3H/He mice [20]; third, based on our previous study, significant hematotoxicity was observed in C3H/He mice exposed to 150 mg/kg b.w. for four weeks.…”