Carlson E A, Li Y, Zelikoff J T
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA.
Toxicol Appl Pharmacol. 2004 Nov 15;201(1):40-52. doi: 10.1016/j.taap.2004.04.018.
Exposure to the environmental contaminant benzo[a]pyrene (BaP) results in suppression of immune function in both mammalian and fish species. This laboratory has previously demonstrated that a single intraperitoneal (IP) injection of BaP reduced lymphocyte proliferation, phagocyte-mediated superoxide generation, and antibody-forming cell (AFC) numbers in Japanese medaka (Oryzias latipes). The objective of the current study was to determine the role of BaP metabolism in the observed immunosuppression. Results from rodent studies have suggested that BaP elicits its immunotoxic effects via upregulation of cytochrome P4501A1 (CYP1A1) and the subsequent production of immunosuppressive BaP metabolites. In this study, exposure of medaka to 200 microg BaP/g BW significantly induced CYP1A expression or activity within lymphoid tissue 48 h post-IP injection; induction was observed specifically within distinct subpopulations of kidney mononuclear cells. Concurrent injection of fish with BaP and the CYP1A1 inhibitors alpha-naphthoflavone (ANF) or dehydroepiandrosterone (DHEA) resulted in inhibition of renal EROD activity and amelioration of BaP-induced suppression of medaka AFC numbers. Results of this study suggest that (1) BaP-induced suppression of medaka humoral immunity relies upon the CYP1A-catalyzed production of immunotoxic BaP metabolites and (2) BaP metabolites may be created in situ, directly by specific cells within kidney lymphoid tissue. Thus, apparently, mechanisms involved in BaP-induced immunosuppression have been phylogenetically conserved from fish to mammals.
接触环境污染物苯并[a]芘（BaP）会导致哺乳动物和鱼类的免疫功能受到抑制。本实验室先前已证明，单次腹腔注射BaP会降低日本青鳉（Oryzias latipes）的淋巴细胞增殖、吞噬细胞介导的超氧化物生成以及抗体形成细胞（AFC）数量。本研究的目的是确定BaP代谢在观察到的免疫抑制中的作用。啮齿动物研究的结果表明，BaP通过上调细胞色素P4501A1（CYP1A1）以及随后产生免疫抑制性BaP代谢产物来引发其免疫毒性作用。在本研究中，给青鳉腹腔注射200μg BaP/g体重后48小时，青鳉接触BaP会显著诱导淋巴组织中CYP1A的表达或活性；在肾脏单核细胞的不同亚群中特异性观察到诱导现象。同时给鱼类注射BaP和CYP1A1抑制剂α-萘黄酮（ANF）或脱氢表雄酮（DHEA）会导致肾脏EROD活性受到抑制，并改善BaP诱导的青鳉AFC数量的抑制。本研究结果表明：（1）BaP诱导的青鳉体液免疫抑制依赖于CYP1A催化产生免疫毒性BaP代谢产物；（2）BaP代谢产物可能在肾脏淋巴组织内由特定细胞直接原位产生。因此，显然，BaP诱导免疫抑制所涉及的机制在从鱼类到哺乳动物的进化过程中是保守的。
