Table 2.

Timeline of proposed key discoveries, as the exciting “AHR-signaling story” developed.

Year	Discovery
1956	“Benzpyrene hydroxylase” activity induced by PAHs in rat liver
1962	Benzpyrene hydroxylase activity induced throughout rat GI tract by oral benzpyrene
1968	“AHH activity” assay designed; AHH induction by PAHs in fetal hamster cell cultures
1969	Differences in AHH inducibility by PAHs between inbred strains of mice
1970	PAH-induced AHH activity represents a cytochrome P450 (P₁-450)
1972	PAH-induced AHH activity in B6 × D2 crosses exhibits predominantly Mendelian inheritance
1972	In utero AHH induction in fetuses by treatment of mother with PAHs
1973–1989	Importance of AHR-mediated CYP1 shown for cancer, mutagenesis, toxicity, and teratogenesis
1974	Evidence of AHR, based on dose-response curve: AHH induction as a function of TCDD concentration in B6 vs D2 inbred mouse strains
1976	Radiolabeled TCDD binding assay detects cytosolic AHR
1979	Development of benzo[a]pyrene-resistant clones in Hepa-1 cells: c1 & c37, c2, and c4
1980	AHR-mediated CYP1A1-induced sister-chromatid-exchange detected in GD7.5 embryo
1981, 1989	AHR-mediated P₁-450 induction proposed to be involved in inflammatory process
1982	Intranuclear appearance of radiolabeled TCDD (AHR) asspcoated with P₁-450 induction
1988, 1998	AHR-mediated CYP1A1 induction demonstrated in GD0.5 one-cell zygote
1991	Mouse Arnt gene cloned (human ARNT gene shortly thereafter)
1991	The term “bHLH/PAS” was first coined
1992	Mouse Ahr gene cloned (human AHR gene shortly thereafter)
1995	Creation of first of several Ahr(−/−) knockout mouse lines
1996	Standardized gene nomenclature for CYP genes in all species becomes well established
2005	AHR-CYP1 axis demonstrated in cultured ES cells
2008, 2013	Underscoring the importance of AHR-CYP1 axis in LM second-messenger pathways involving innumerable critical life events — in virtually every organ, tissue and cell-type