title: Polychlorinated biphenyls (PCBs) inhibit hepcidin expression through an estrogen-like effect associated with disordered systemic iron homeostasis.
abstract: Polychlorinated biphenyls (PCBs), with 209 congeners, are a large family of persistent organic pollutants. PCBs elicit a wide range of toxicities, such as neurotoxicity, hepatoxicity, oncogenicity, and endocrine-disrupting effects. However, an understanding of the potential disruption of systematic iron metabolism by PCBs is still limited. To maintain iron homeostasis, the hepcidin-ferroportin (FPN) axis is critically important, and hepcidin is the central governor in guiding dietary iron absorption and iron egress from macrophages. Hepcidin is secreted by hepatocytes and binds to FPN to promote its degradation. Dysregulation of hepcidin gives rise to disordered iron homeostasis, associated with diverse diseases including anemia and β-thalassemia. Our previous study demonstrated that there is an estrogen response element (ERE) within the promoter of hepcidin gene and that its expression is regulated by estrogen. In the current study, we demonstrated that both PCB153 and PCB126 greatly suppress hepcidin expression in HepG2 cells, with a greater repression occurring in cells upon PCB126 treatment. Further studies uncovered that both PCB153 and PCB126 harbor estrogenic activity and that the estrogenic activity of PCB126 was stronger than that of PCB153 in HepG2 cells. Mechanistic investigation revealed that PCBs suppress hepcidin transcription through a functional ERE within the hepcidin promoter, analogous to the action of 17β-estradiol. Moreover, hepatic hepcidin was downregulated in wild-type mice upon PCB126 administration, coupled with elevated serum iron content as well as reduced hepatic and splenic iron mass. These changes were not replicated in hepcidin-deficient mice upon PCB administration. Additionally, hepatocytes were observed with severe accumulation of lipid droplets in the livers of mice challenged with PCB126, irrespective of the presence of hepcidin. To summarize, our results have deciphered a suppressive role of PCBs in restraining the expression of hepcidin through mimicking estrogenic activity and revealed a novel property of PCBs in disrupting systemic iron metabolism. This study also unearthed a PCB-mediated connection linking estrogen-like activity, iron effects, and lipid homeostasis.
authors: †College of Biological and Environmental Engineering, Zhejiang University of Technology, Hangzhou 310032, China.|‡State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
authors: Yi
authors: Y
authors: Qian
authors: ‡State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.|§Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
authors: Shuping
authors: S
authors: Zhang
authors: ‡State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
authors: Wenli
authors: W
authors: Guo
authors: ‡State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
authors: Juan
authors: J
authors: Ma
authors: ‡State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
authors: Yue
authors: Y
authors: Chen
authors: ‡State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
authors: Lei
authors: L
authors: Wang
authors: †College of Biological and Environmental Engineering, Zhejiang University of Technology, Hangzhou 310032, China.
authors: Meirong
authors: M
authors: Zhao
authors: ‡State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
authors: Sijin
authors: S
authors: Liu
mesh_terms: D000818:Animals; D055418:Bone Morphogenetic Protein 6 / Q000378:metabolism; D004967:Estrogens / Q000502:physiology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D056945:Hep G2 Cells; D064451:Hepcidins / Q000235:genetics*; D006706:Homeostasis; D006801:Humans; D007249:Inflammation / Q000139:chemically induced; D007501:Iron / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects; D011078:Polychlorinated Biphenyls / Q000633:toxicity*
chemical_list: C525816:BMP6 protein, human; D055418:Bone Morphogenetic Protein 6; D004967:Estrogens; D064451:Hepcidins; D011078:Polychlorinated Biphenyls; D007501:Iron