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Abstract
In adult mice the cytochrome P450 Cyp1a1 gene is not constitutively expressed but is highly inducible by foreign compounds acting through the aryl hydrocarbon (Ah) receptor. However, the expression profile of the Cyp1a1 gene in the developing embryo is not well under-stood. Using established transgenic mouse lines where 8.5 kb of the rat CYP1A1 promoter is cloned upstream of the lacZ reporter gene (1), we describe the expression of the CYP1A1-driven reporter gene in all tissues through-out stages E7-E14 of embryonic development. In contrast to the absence of constitutive Cyp1a1 and lacZ transgene expression in tissues of the adult mouse, a constitutive cell-specific and time-dependent pattern of CYP1A1 promoter activity was observed in the embryo. This expression pattern was confirmed as reflecting the endogenous gene by measuring Cyp1a1 mRNA levels and protein expression by immunohistochemistry. The number of cells displaying endogenous CYP1A1 activity could be increased in the embryo upon xenobiotic challenge, but only within areas where the CYP1A1 promotor was already active. When reporter mice were bred onto a genetic background expressing a lower affinity form of the Ah receptor (DBA allele), transgene and murine Cyp1a1 protein expression were both attenuated in the adult mouse liver upon xenobiotic challenge. By comparison, constitutive CYP1A1 promoter activity in the embryo was identical in the presence of either the high or low affinity Ah receptor. These novel data suggest that the Cyp1a1 protein may play a role in murine development and that regulation of the Cyp1a1 gene during this period is either through the action of a high affinity Ah receptor ligand or by an alternative regulatory pathway.
Highlights
The mammalian cytochrome P450 (CYP)1-dependent monooxygenase system plays a key role in the metabolism and disposition of environmental chemicals
The mechanism of Cyp1a1 gene regulation involves the binding of the foreign compound to a cytoplasmic receptor, the aryl hydrocarbon (Ah) receptor, which dissociates from the heat shock protein-90, allowing it to enter the nucleus where it dimerizes with the transcription factor Ah receptor nuclear translocator (ARNT), to activate the promoters of responsive genes
CYP1A1 Promoter Activity Is a Legitimate Reporter of Cyp1a1 mRNA and Protein Expression— the temporal and spatial pattern of promoter activity in the pAHIR1galactosidase transgenic mice was conserved in different transgenic lines in the adult mouse [1] and in the developing embryo, we investigated whether lacZ staining reflected genuine Cyp1a1 expression
Summary
The mammalian cytochrome P450 (CYP)1-dependent monooxygenase system plays a key role in the metabolism and disposition of environmental chemicals. In contrast to the absence of constitutive Cyp1a1 and lacZ transgene expression in tissues of the adult mouse, a constitutive cell-specific and time-dependent pattern of CYP1A1 promoter activity was observed in the embryo.
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