Toxicity of tetrachlorobisphenol A interfering with craniofacial cartilage development by inhibiting RXR activity in...

Tetrachlorobisphenol A (TCBPA), a prevalent halogenated flame retardant detected in human serum and breast milk, poses significant exposure risks during developmental windows. While recognized for reproductive toxicity, its impact on craniofacial development remains unexplored. This study investigated the effects of TCBPA (0.5, 0.6, and 0.7 mg/L) on zebrafish cartilage development during craniofacial bone development (11-96 h post-fertilization). At experimental concentrations, TCBPA induced a range of developmental issues, notably significant craniofacial deformities, which were characterized by abnormal specifications and morphology of Meckel's and ceratohyal cartilages. Additionally, qPCR results revealed that TCBPA exposure led to the down-regulation of genes related to cartilage development. Moreover, it antagonized retinoid X receptor subtype beta-a (RXRba), a key receptor in the retinoic acid (RA) signaling pathway, leading to suppressed expression of downstream target genes essential for cartilage development. TUNEL staining further demonstrated that TCBPA exposure triggered excessive apoptosis of zebrafish craniofacial chondrocytes, a finding corroborated by qPCR results indicating altered expression of apoptosis-related genes. This phenomenon may be attributed to the collaborative involvement of RXRs and peroxisome proliferator-activated receptor gamma (PPARγ) in regulating cell survival, differentiation, and apoptosis. The antagonism of TCBPA on RXRba was also validated in a rescue experiment using Bexarotene, a high affinity agonist of RXRs. In conclusion, TCBPA inhibits the expression of genes crucial to cartilage development by antagonizing RXRba activity. It also induces abnormal apoptosis of chondrocytes through other signaling pathways mediated by RXRs, resulting in craniofacial cartilage toxicity in zebrafish.