Abstract
Chronic exposure to benzene is known to be associated with haematotoxicity and the development of aplastic anaemia and leukaemia. However, the mechanism underlying benzene‐induced haematotoxicity, especially at low concentrations of chronic benzene exposure has not been well‐elucidated. Here, we found that increased autophagy and decreased acetylation occurred in bone marrow mononuclear cells (BMMNCs) isolated from patients with chronic benzene exposure. We further showed in vitro that benzene metabolite, hydroquinone (HQ) could directly induce autophagy without apoptosis in BMMNCs and CD34+ cells. This was mediated by reduction in acetylation of autophagy components through inhibiting the activity of acetyltransferase, p300. Furthermore, elevation of p300 expression by Momordica Antiviral Protein 30 Kd (MAP30) or chloroquine reduced HQ‐induced autophagy. We further demonstrated that in vivo, MAP30 and chloroquine reversed benzene‐induced autophagy and haematotoxicity in a mouse model. Taken together, these findings highlight increased autophagy as a novel mechanism for benzene‐induced haematotoxicity and provide potential strategies to reverse this process for therapeutic benefits.
Highlights
Chronic exposure to either high‐ or low‐dose benzene, a widely used industrial chemical and omnipresent environmental pollutant, can cause bone marrow suppression and may result in various diseases including aplastic anaemia, myelodysplastic syndrome, and leukaemia.[1]
We further show that Momordica Antiviral Protein 30 Kd (MAP30), a ribosome‐inactivating protein isolated from dietary bitter melon, can increase p300 and reverse the autophagy induced by HQ
We found that acetylation of LC3 was predominant in LC3‐I rather than LC3‐II (Figure 1C), and the acetylation of LC3 (Figure 1C) and histone H3 (Figure 1D) were decreased in bone marrow mononuclear cells (BMMNCs) from patients with chronic benzene exposure compared with those from healthy donors
Summary
Chronic exposure to either high‐ or low‐dose benzene, a widely used industrial chemical and omnipresent environmental pollutant, can cause bone marrow suppression and may result in various diseases including aplastic anaemia, myelodysplastic syndrome, and leukaemia.[1] It has been suggested that benzene metabolites can cause damage to haematopoietic cells via multiple mechanisms such as chromosomal aberration and covalent binding, epigenetic regulation, oxidative stress, and disruption of tumour surveillance.[2] We have shown that exposure to high‐dose benzene or its metabolite hydroquinone (HQ) leads to haematopoietic toxicity through induction of apoptosis in vivo and in vitro.[3,4] it remains unknown how low concentration of benzene exposure results in haematopoietic toxicity. We first demonstrate that increased autophagy and deacetylation of autophagic protein LC3 occur in bone marrow mononuclear cells (BMMNCs) isolated from patients with chronic low‐dose benzene exposure. Chronic exposure to low‐dose benzene in mice results in deacetylation, increased autophagy and haematopoietic toxicity, which can be reversed by treatment with MAP30 and a classical autophagy inhibitor chloroquine (CQ)
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