Congener Variation of Genetic Dependent-Developmental Toxicology in Two Emerging Classes of Dioxin-like Compounds

Emerging
classes of dioxin-like compounds (DLCs) like hydroxylated/methoxylated
polybrominated diphenyl ethers (HO-/MeO-PBDEs) and polychlorinated
diphenyl sulfides (PCDPSs) could lead to diverse adverse outcomes
in humans and wildlife, yet knowledge gaps exist in their molecular
mechanisms associated with different structures following early life
environmental exposure. This study integrated a genetic knockout technique
and concentration-dependent reduced zebrafish transcriptome approach
(CRZT) to unravel the toxicological pathways underpinning developmental
toxicity of four HO-/MeO-PBDEs and five PCDPSs at environmentally
relevant doses. Generally, the dependence of aryl hydrocarbon receptor
(AhR) on the embryotoxicity and transcriptomic potencies induced by
the HO-PBDEs and PCDPSs varied across different congeners. The knockout
of the ahr2 gene led to 1.02- to 76.48-fold decreases
of DLC-induced embryotoxicities and reduced the transcriptome-based
potencies ranging from 1.38 to 2124.74 folds in the CRZT test. The
fold changes denoting AhR-mediated potentials significantly increased
with the increasing chlorination degrees of MeO-PBDEs and PCDPSs (p < 0.05). Moreover, ahr2 knockout primarily
affected the DLC-induced early molecular responses relevant to DNA
damage, enzyme activation, and organ development. Our integrated approach
revealed the differential role of AhR in mediating the developmental
toxicity of emerging DLCs possessing varied structures at environmentally
relevant doses.