Adverse Reproductive Outcomes in the Transgenic Ah Receptor-Deficient Mouse

Abstract

The aryl hydrocarbon receptor (AHR) is a transcriptional regulatory protein that binds to upstream DNA response elements of target genes. Activation of the AHR by binding of ligands such as polyhalogenated dioxins, furans, and PCBs is associated with a wide range of adverse biological outcomes, including cancer, immune deficiencies, embryo/fetotoxicity, and reproductive toxicity. Investigations of the diverse biological responses mediated by the AHR led to production of a transgenic mouse in which the gene coding for the AhR was inactivated. AHR-deficient mice were fertile and at maturity exhibited immune system impairment and hepatic fibrosis. Our laboratory received 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 combinations. Although male and female −/− adults were fertile, the −/− females had difficulty maintaining conceptuses during pregnancy, surviving pregnancy and lactation, and rearing pups to weaning. Only 46% of the 39 pregnant −/− females successfully raised pups to weaning. The −/− pups showed poor survival during lactation (average death rate per litter was 16%) and after weaning (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 Postnatal Day 45. Across all litters the sex ratios and genotypic frequencies were comparable to expected values. Reproductive success was adversely affected inAhr-null females and conceptuses. Additional study is needed to reveal the etiology of these effects.