Skeletal toxicity has been reported following exposure to polychlorinated biphenyl (PCB) mixtures. However, molecular mechanisms remain poorly understood. We exposed groups of male 4-5-week-old Sprague-Dawley rats to 3,3', 4, 4', 5-pentachlorobiphenyl (PCB 126), a dioxin-like coplanar PCB congener by a single i.p. injection of 5 µmol/kg in soy oil vehicle or vehicle alone. After 4 weeks, rats were euthanized. PCB exposure resulted in hypocalcemia (P < 0.05) and significant increases in serum PTH without changes in serum phosphorous. Hyperparathyroidism was accompanied by increased expression of mRNAs of vitamin D3 metabolizing cytochrome P450 enzymes CYP27B1 and CYP24 in the kidney (P < 0.05). PCB exposure also reduced body weight, serum IGF-1, and hepatic expression of mRNAs encoding the male-specific GH-pattern-regulated CYP2C11 and CYP3A2 relative to controls (P < 0.05). PCB exposure reduced long bone length, diameter, and surface area, but increased trabecular thickness and volume (P < 0.05). Serum osteocalcin (P < 0.05), a marker and a regulator of bone formation, was reduced, but PCB exposure had no effect on the bone resorption marker RatLaps. Exposure of human intestinal Caco-2 cells to 10-100 nM PCB 126 in the presence of vitamin D3 resulted in inhibition of mRNAs for the calcium transporters TRPV6 and PMCA1b (P < 0.05). In addition, PCB 126 suppressed osteoblastogenesis in primary bone marrow mesenchymal stem cell cultures which was blunted by the AhR antagonist CH-223191. These data provide novel evidence that skeletal toxicity after exposure to PCB 126 is a result of disruption of calcium homeostasis and the GH-IGF-1 axis, and involves direct AhR-mediated effects on bone formation.

中文翻译：

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成长中的雄性大鼠暴露于共面PCB 126所产生的骨骼毒性与钙稳态和GH-IGF-1轴的破坏以及对骨形成的直接影响有关。

据报道，暴露于多氯联苯（PCB）混合物会对骨骼产生毒性。但是，分子机制仍然知之甚少。我们通过单次ip注射5 µmol，将成群的4-5周大的Sprague-Dawley大鼠暴露于3,3'，4、4'，5-五氯联苯（PCB 126），这是一种二恶英样共面PCB同类物。 / kg在大豆油运输工具或单独的运输工具中。4周后，对大鼠实施安乐死。多氯联苯暴露导致低血钙（P <0.05），血清PTH显着增加而血清磷无变化。甲状旁腺功能亢进症伴有肾脏中维生素D3代谢细胞色素P450酶CYP27B1和CYP24的mRNA表达增加（P <0.05）。PCB暴露也可减轻体重，血清IGF-1，CYP2C11和CYP3A2男性特异性GH模式调控的mRNA相对于对照组的肝表达（P <0.05）。PCB暴露减少了长骨的长度，直径和表面积，但增加了小梁的厚度和体积（P <0.05）。血清骨钙素（P <0.05）是骨形成的标志物和调节剂，其含量降低了，但PCB暴露对骨吸收标志物RatLaps没有影响。在维生素D3存在下将人肠道Caco-2细胞暴露于10-100 nM PCB 126中会导致钙转运蛋白TRPV6和PMCA1b的mRNA受到抑制（P <0.05）。此外，PCB 126抑制了原代骨髓间充质干细胞培养物中的成骨细胞生成，该培养物被AhR拮抗剂CH-223191钝化。