In our ES08147 grant, the goals are to: [1] study the toxicity of benzo[a]pyrene (BaP) vs. dioxin in various, tissues (bone marrow, liver, developing embryo) of the Cyp1a1(-/-) knockout and Cyp1a1(+/+) wild-type mouse as a function of dose of the environmental pollutant and route of administration, and [2] create mouse lines having exclusively mitochondrial CYP1A 1 (mt1A1) vs. exclusively microsomal CYP1A1 (mc1A1) to study such toxicity further. Preliminary data from Specific Aim #1 studies, however, have convinced us that we should supplement our ES08147 research with double and triple knockouts of the Cyp1genes as soon as possible. Previous results with cell culture or in vitro studies differ from that in the intact animal. For example, we found that Cyp1a1(-/-) mice are strikingly sensitized to oral BaP-induced immunotoxicity. Also, Cyp1a1(-/-) showed only modest protection against BaP-induced liver damage, compared with Cyp1a1(+/+) mice, whereas BaP-DNA adducts were unexpectedly >4-fold higher in Cyp1a1(-/-) mice. It would appear that the biological functions of the dioxin-inducible CYP1 enzymes are more redundant than we had imagined, with overlapping substrate specificities of all three enzymes, plus unique tissue- and cell type-specific locations of the three enzymes, thereby making it extremely difficult to assess the role of CYP1A1 in environmental toxicity using only the Cyp1a1(-/-) mouse. Thus, the function of CYP1A1 in environmental toxicity is best studied with and without the presence of CYP1A2 and/or CYP1B1. Conventional and Cre-inducible knockout Cyp1 mice provide the systems to tease apart the contribution of each CYP1 enzyme that contributes to cell type-specific toxicity. Therefore, concomitantly with the ES08147 grant, we believe it is imperative that we also: [1] generate conventional and inducible Cyp1a1/1a2(-/-) and Cyp1a1/1bl(-/-) double-knockout lines and the Cyp1a1/1a2/1b1(-/-) triple-knockout mouse lines; and [2] assess BaP- vs dioxin-induced toxicity of the marrow, liver and developing embryo in these double- and triple-knockout lines. Our original aim to generate the mt1A1 and mc1A1 mice and then study BaP vs dioxin toxicity in these lines remains unchanged.
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