Mechanisms by which benzo[a]pyrene, an environmental carcinogen, suppresses B cell lymphopoiesis.
The capacity for polycyclic aromatic hydrocarbons (PAH) to suppress immune cell function has been well documented. Nevertheless, mechanisms responsible for PAH immunosuppression and potential effects of PAH on lymphocyte development (lymphopoeisis) remain poorly defined. Murine bone marrow cultures were used in the present studies to determine if and by what mechanism(s) benzo[a]pyrene (B[a]P), a prototypic and highly carcinogenic PAH, suppresses B cell lymphopoiesis. Emphasis was placed on similarities between the processes leading to transformation and immunosuppression and on a possible role for programmed cell death (apoptosis) in B[a]P lymphotoxicity. Data presented herein indicate that: (1) B[a]P suppresses B cell lymphopoiesis in bone marrow cultures at extremely low concentrations (10(-8) M); (2) benzo[e]pyrene, the relatively noncarcinogenic congener of B[a]P, is approximately 1000 times less potent than B[a]P in suppressing B cell lymphopoiesis; (3) bone marrow cells from PAH-resistant DBA/2 mice are less sensitive to B[a]P than cells from C57BL/6 mice; (4) B[a]P induces preB cell apoptosis; and (5) alpha-naphthaflavone, an inhibitor of Ah-receptor dependent, P450 isoenzyme activity, blocks B[a]P-mediated preB cell apoptosis and inhibits B[a]P-dependent suppression of lymphopoiesis. The results support the hypothesis that B[a]P suppression of B cell lymphopoiesis is mediated at least in part by the induction of programmed cell death and that the Ah receptor and/or P450 isoenzymes are involved in this process. The results suggest the potential for PAH to affect development of the B lymphocyte repertoire.
Hardin
J A
JA
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115.
Hinoshita
F
F
Sherr
D H
DH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects* / Q000473:pathology; D001564:Benzo(a)pyrene / Q000037:antagonists & inhibitors / Q000633:toxicity*; D001571:Benzoflavones / Q000494:pharmacology; D001580:Benzopyrenes / Q000633:toxicity; D001853:Bone Marrow / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation; D007108:Immune Tolerance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug / Q000187:drug effects
D001571:Benzoflavones; D001580:Benzopyrenes; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug; D001564:Benzo(a)pyrene; C011512:alpha-naphthoflavone; C026487:benzo(e)pyrene