muconaldehyde and Hematologic-Diseases

A metabolite of benzene, trans,trans-muconaldehyde (MUC) was found to be a strong inhibitor of gap junction intercellular communication (GJIC) with potency similar to that of chlordane. Hydroquinone and the MUC metabolite OH-M-CHO were also strong inhibitors of GJIC. The other MUC metabolites tested, CHO-M-COOH and OH-M-COOH had weak effects on GJIC, while COOH-M-COOH had no effect. Benzene showed no effect on GJIC. The relative potency of the metabolites on GJIC is similar to what is observed with regard to hematotoxic effects. The effect of MUC on GJIC took place in parallel with a strong cellular loss of connexin 43. Substances found to inhibit connexin 43 dependent GJIC have been shown to disrupt normal hematopoietic development. The finding that benzene metabolites interfere with gap junction functionality, and especially the loss of connexin 43 induced by MUC, should be considered concerning the mechanism of benzene-induced hematotoxicity.

Topics: Aldehydes; Animals; Benzene; Cell Communication; Cell Line; Gap Junctions; Hematologic Diseases; Hydroquinones; Leukemia

6-Hydroxy-trans,trans-2,4-hexadienal (CHO-M-OH) is a metabolite of trans,trans-muconaldehyde (muconaldehyde or MUC), a microsomal hematotoxic ring-opened metabolite of benzene. In the present study, the toxicity of CHO-M-OH was examined. In order to assess potential toxic effects of CHO-M-OH on the maturation of erythroid cells in the bone marrow, 10-week-old male CD-1 mice were administered CHO-M-OH intraperitoneally and 59Fe incorporation into erythrocytes was measured. The uptake of 59Fe by erythroid cells was significantly inhibited at doses of 20, 25, and 30 mg/kg. There was no inhibition of 59Fe incorporation at a dose of 15 mg/kg. In other hematotoxicity studies, bone marrow cellularity, peripheral blood cells, and sulfhydryl contents in bone marrow cells were examined in mice administered CHO-M-OH intraperitoneally. An increase in the white blood cell count was observed in mice treated with 5 mg/kg/day for 16 consecutive days, while bone marrow cellularity and red blood cell parameters were not changed. Administration of 10 mg/kg/day for 16 consecutive days caused a significant decrease in sulfhydryls of bone marrow cells but no changes in bone marrow cellularity and peripheral blood parameters compared with controls. At a dose of 25 mg/kg/day for 4 days, there was a significant decrease in nucleated bone marrow cells. The white blood cell count, mainly lymphocytes, also significantly decreased. Our results indicate that CHO-M-OH is a hematotoxin in mice and conceivably could play a role in benzene toxicity.

Topics: Aldehydes; Alkadienes; Animals; Bone Marrow; Hematologic Diseases; Iron; Iron Radioisotopes; Male; Mice