Adverse reproductive outcomes in the transgenic Ah receptor-deficient mouse

The aryl hydrocarbon receptor (AHR) is a transcriptional regulatory protein that binds to upstream DNA response elements of target genes. Activation o f the AHR by binding of ligands such as polyhalogenated dioxins, furans, an d PCBs is associated with a wide range of adverse biological outcomes, incl uding cancer, immune deficiencies, embryo/fetotoxicity, and reproductive to xicity. Investigations of the diverse biological responses mediated by the AHR led to production of a transgenic mouse in which the gene coding for th e AhR was inactivated. AHR-deficient mice were fertile and at maturity exhi bited immune system impairment and hepatic fibrosis. Our laboratory receive d several of these homozygous knockout (-/-) mice and mated them with wild- type (+/+) C57BL/6N mice to generate large numbers of heterozygotes (+/-)). The -/- males were then mated with a total of 45 heterozygous +/- females. Offspring of these matings were genotyped and mated in all genotypic combi nations. Although male and female -/- adults were fertile, the -/- females had difficulty maintaining conceptuses during pregnancy, surviving pregnanc y and lactation, and rearing pups to weaning. Only 46% of the 39 pregnant - /- females successfully raised pups to weaning. The -/- pups showed poor su rvival during lactation (average death rate per litter was 16%) and after w eaning (26.5% of the 230 weaned -/- pups died within 2 weeks). Only 39% of the implantations in uteri of -/- dams resulted in offspring surviving to P ostnatal Day 45. Across all litters the sex ratios and genotypic frequencie s were comparable to expected values. Reproductive success was adversely af fected in Ahr-null females and conceptuses. Additional study is needed to r eveal the etiology of these effects.