A luciferase reporter gene assay and aryl hydrocarbon receptor 1 genotype predict the LD50 of polychlorinated biphenyls in avian species

作者：Manning Gillian E; Farmahin Reza; Crump Doug; Jones Stephanie P; Klein Jeff; Konstantinov Alex; Potter Dave; Kennedy Sean W^*

来源：Toxicology and Applied Pharmacology, 2012, 263(3): 390-401.

DOI：10.1016/j.taap.2012.07.016

• Polychlorinated biphenyl
• Aryl hydrocarbon receptor
• Luciferase reporter gene assay
• Cytochrome P450 1A induction
• Embryotoxicity
• Birds

Birds differ in sensitivity to the embryotoxic effects of polychlorinated biphenyls (PCBs), which complicates environmental risk assessments for these chemicals. Recent research has shown that the identities of amino acid residues 324 and 380 in the avian aryl hydrocarbon receptor 1 (AHR1) ligand binding domain (LBD) are primarily responsible for differences in avian species sensitivity to selected dibenzo-p-dioxins and furans. A luciferase reporter gene (LRG) assay was developed in our laboratory to measure AHR1-mediated induction of a cytochrome P450 1A5 reporter gene in COS-7 cells transfected with different avian AHR1 constructs. In the present study, the LRG assay was used to measure the concentration-dependent effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and PCBs 126, 77, 105 and 118 on luciferase activity in COS-7 cells transfected with AHR1 constructs representative of 86 avian species in order to predict their sensitivity to PCB-induced embryolethality and the relative potency of PCBs in these species. The results of the LRG assay indicate that the identity of amino acid residues 324 and 380 in the AHR1 LBD are the major determinants of avian species sensitivity to PCBs. The relative potency of PCBs did not differ greatly among AHR1 constructs. Luciferase activity was significantly correlated with embryolethality data obtained from the literature (R-2 %26gt;= 0.87, p%26lt;0.0001). Thus, the LRG assay in combination with the knowledge of a species%26apos; AHR1 LBD sequence can be used to predict PCB-induced embryolethality in potentially any avian species of interest without the use of lethal methods on a large number of individuals.

• 出版日期2012-9-15