HUMAN T-CELLS ARE HIGHLY SENSITIVE TO SUPPRESSION OF MITOGENESIS BY POLYCYCLIC AROMATIC-HYDROCARBONS AND THIS EFFECT IS DIFFERENTIALLY REVERSED BY ALPHA-NAPHTHOFLAVONE

The immunosuppressive effects of polycyclic aromatic hydrocarbons (PAH s) on immune responses in rodents, both in vivo and in vitro, have bee n widely documented. However, few studies have addressed the immunotox icity of PAHs in the human system. In this report, we examined the tox ic effects of nine different PAHs on human peripheral blood T cell mit ogenesis. We found that benzo(a)pyrene (BaP), 3-methylcholanthrene (3- MC), and 7,12-dimethylbenz(a)anthracene (DMBA) were highly immunotoxic in the human system, while dibenz(a,c)anthracene (DAC) and dibenz(a,h )anthracene (DAH) were of intermediate toxicity, 9,10-dimethylanthrace ne (DMA), benzo(e)pyrene (BeP), and benz(a)anthracene (BA) were mildly immunotoxic, and anthracene (ANTH) had no measureable toxicity at the concentrations tested. Our results using human lymphocytes differed f rom previous studies in rodents, in that BaP and 3-MC were the most im munotoxic PAHs in the human mitogenesis assay, while DMBA has long bee n regarded as the PAH that is most potently toxic to rodent T cell res ponses. We also showed that alpha-naphthoflavone (ANF), which function s as both an Ah receptor antagonist and an inhibitor of cytochrome P45 0 activity, was able to block the suppressive effects of both BaP and DMBA, but not 3-MC. This suggests that the immunotoxicity of 3-MC may be mediated through a different mechanism than BaP or DMBA. Addition o f four different BaP metabolites directly to cultures of human mononuc lear cells showed that the 7,8-dihydrodiol metabolite was the most tox ic, and that this toxicity could be completely blocked by equimolar an d 10-fold greater concentrations of ANF. The 7,8-dihydrodiol metabolit e was probably further metabolized to the 7,8-diol epoxide, the toxici ty of which could not be effectively reversed by ANF. The 4,5-epoxide metabolite was apparently cytotoxic at high concentrations (10 mu M), while the 7-hydroxy metabolite had no overtly negative effects on prol iferation. (C) 1996 Academic Press, Inc.