The aryl hydrocarbon receptor directs the differentiation of murine progenitor blastomeres

Abstract

Key regulatory decisions during cleavage divisions in mammalian embryogenesis determine the fate of preimplantation embryonic cells. Single-cell RNA sequencing of early-stage—2-cell, 4-cell, and 8-cell—blastomeres show that the aryl hydrocarbon receptor (AHR), traditionally considered as an environmental sensor, directs blastomere differentiation. Disruption of AHR functions in Ahr knockout embryos or in embryos from dams exposed to dioxin, the prototypic xenobiotic AHR agonist, significantly impairs blastocyst formation, causing repression and loss of transcriptional heterogeneity of OCT4 and CDX2 and incidence of nonspecific downregulation of pluripotency. Trajectory—the path of differentiation—and gene variability analyses further confirm that deregulation of OCT4 functions and changes of transcriptional heterogeneity resulting from disruption of AHR functions restrict the emergence of differentiating blastomeres in 4-cell embryos. It appears that AHR directs the differentiation of progenitor blastomeres and that disruption of preimplantation AHR functions may significantly perturb embryogenesis leading to long-lasting conditions at the heart of disease in offspring’s adulthood.

The Ah Receptor from Toxicity to Therapeutics: Report from the 5th AHR Meeting at Penn State University, USA, June 2022

“…Interestingly, the AHR also regulates blastocyst formation as shown by the decrease in blastocyst numbers in KO models, but also in the case of TCDD treatment, suggesting a competition of this xenobiotic with endogenous ligands. As an illustration, Oct4 is expressed from the “four cells” stage onwards, while AHR expression decreases at this stage of development and practically disappears at the “eight cells” stage [ 22 ].…”