Gender- and age-specific cytotoxic susceptibility to benzene metabolites in vitro

Benzene, a widely used compound, is a known carcinogen and hematopoietic toxicant. Several studies have shown gender and age differences in the responses to benzene-induced hematotoxicity. It is not known if these differences in response are due to age- or gender-associated metabolic differences or to age- or gender-associated differences in the susceptibilities of the target cells. In order to address this issue, mouse colony-forming units-erythroid (CFU-e, an erythroid precursor cell particularly susceptible to benzene toxicity) were cultured in the presence of either individual benzene metabolites or binary mixtures of these metabolites. CFU-e were obtained from unexposed age-matched adult male and female (both virgin and pregnant) Swiss Webster (SW) mice and from SW male and female 16-day fetuses. The metabolites used were phenol, hydroquinone, catechol, benzoquinone, and trans, trans-muconic acid. The concentrations of the individual metabolites used were 10, 20, and 40 microM. Binary mixtures of metabolites were prepared using the lowest concentrations of the individual metabolites that caused cytotoxicity. These concentrations were 10 microM for hydroquinone, catechol, and benzoquinone, and 40 microM for phenol and muconic acid. In general, the CFU-e from adult females (both virgin and pregnant) were more resistant to the toxic effects of the individual metabolites than CFU-e from other subjects. CFU-e from adult males were more susceptible to the cytotoxic effects of hydroquinone and benzoquinone than CFU-e from other subjects and CFU-e from both male and female fetuses were highly sensitive to the toxic effects of catechol. On the other hand, CFU-e from adult males were less susceptible to the cytotoxic effects of catechol than CFU-e from other subjects. Similar results were observed with binary mixtures of metabolites. CFU-e from adult males were more susceptible to the binary mixtures than CFU-e from virgin females and CFU-e from fetal males were more susceptible than CFU-e from fetal females. In addition, CFU-e from fetuses were more 'resistant than CFU-e from adults to the cytotoxic effects of those binary mixtures that did not contain catechol. In contrast, binary mixtures containing catechol were more toxic to fetal cells than to adult cells. These results suggest that differences in benzene hematotoxicity associated with gender and age may be due, at least in part, to intrinsic factors at the level of the target cell rather than solely to age- or gender-related differences in the metabolism of benzene.