Skeletal Toxicity of Coplanar Polychlorinated Biphenyl Congener 126 in the Rat is Aryl Hydrocarbon Receptor-Dependent

Epidemiological evidence links polychlorinated biphenyls (PCBs) to skeletal toxicity, however mechanisms whereby PCBs affect bone are poorly studied. In this study, coplanar PCB 126 (5 mumol/kg) or corn oil vehicle was administered to N = 5-6 male and female, wild type (WT) or AhR-/- rats via intraperitoneal injection. Animals were sacrificed after four weeks. Bone length was measured; bone morphology was assessed by micro-computed tomography and dynamic histomorphometry. Reduced bone length was the only genotype specific effect and only observed in males (P < 0.05). WT rats exposed to PCB 126 had reduced serum calcium, and smaller bones with reduced tibial length, cortical area and medullary area relative to vehicle controls (P < 0.05). Reduced bone formation rate observed in dynamic histomorphometry was consistent with inhibition of endosteal and periosteal bone growth. The effects of PCB 126 were abolished in AhR-/- rats. Gene expression in bone marrow and shaft were assessed by RNAseq. Approximately 75% of the PCB regulated genes appeared AhR dependent with 89 genes significantly (P < 0.05) regulated by both PCB 126 and knockout of the AhR gene. Novel targets significantly induced by PCB 126 included Indian hedgehog (Ihh) and connective tissue growth factor (Ctgf/Ccn2), which regulate chondrocyte proliferation and differentiation in the bone growth plate and cell-matrix interactions. These data suggest the toxic effects of PCB 126 on bone are mediated by AhR, which has direct effects on the growth plate and indirect actions related to endocrine disruption. These studies clarify important mechanisms underlying skeletal toxicity of dioxin-like PCBs and highlight potential therapeutic targets.