Evolution of hominin detoxification: Neanderthal and modern human AHR respond similarly to TCDD

Abstract

In studies of hominin adaptations to fire use, the role of the aromatic hydrocarbon receptor (AHR) in the evolution of hominin detoxification, especially regarding toxic smoke components, has been highlighted, including statements that the modern human AHR is significantly better at dealing with smoke toxins. We compared the AHR-controlled induction of cytochrome P450 1A1 (CYP1A1) in cultured cells transfected with an Altai-Neanderthal respectively a modern human reference AHR expression construct, and exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We compared the complete AHR mRNA sequences including the untranslated regions (UTRs), maintaining the original codon usage, in HeLa human cervix epithelial adenocarcinoma cells. Our experiments complement a previous study of the AHR coding region optimized for mammalian codon usage and expressed in rat cells. Our results show no significant difference in CYP1A1 induction by TCDD between Neanderthal and modern human AHR (instead of a previously reported 150-1000 times difference range before), demonstrating that expression in a homologous cellular background is of major importance. The two dose-response curves almost coincide, except for a higher extrapolated maximum induction level for the Neanderthal AHR, possibly caused by a 5-UTR G-variant known from modern humans (rs7796976). Our results are strongly at odds with a major role of the modern human AHR in the evolution of hominin detoxification of smoke components and consistent with our previous study which concluded that efficient detoxification alleles are more dominant in ancient hominins than in modern humans based on 18 relevant genes in addition to AHR.