The inhibition of LPS-induced splenocyte proliferation by ortho-substituted and microbially dechlorinated polychlorinated biphenyls is associated with a decreased expression of cyclin D2

• Published in: Toxicology (Amsterdam) 2004-11, Vol.204 (1), p.61-74
• Main Authors: Smithwick, L. Ashley, Quensen, John F., Smith, Andrew, Kurtz, David T., London, Lucille, Morris, Pamela J.
• Format: Article
• Language: English
• Subjects: Anaerobiosis; Animals; Aroclors - pharmacology; B-cell proliferation; B-Lymphocytes - cytology; B-Lymphocytes - drug effects; B-Lymphocytes - metabolism; Biological and medical sciences; Cell Cycle - drug effects; Cell Division - drug effects; Chlorine; Cyclin D2; Cyclins - biosynthesis; Female; Immunotoxicity; Lipopolysaccharides - antagonists & inhibitors; Medical sciences; Mice; Mice, Inbred C57BL; Ortho substitutions; Polychlorinated biphenyls (PCB); Polychlorinated Biphenyls - chemistry; Polychlorinated Biphenyls - pharmacology; Reductive dechlorination; Spleen - cytology; Structure-Activity Relationship; Toxicology
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2004.06.016

Immunological effects of polychlorinated biphenyls (PCBs) have been demonstrated in our laboratories with the peferential inhibition of lipopolysaccharide (LPS)-induced splenocyte proliferation by ortho-substituted PCB congeners. An investigation of the mechanism behind this immunotoxicity revealed an interruption in the progression of murine lymphocytes from G 0/G 1 into S phase by Aroclor 1242 and the di- ortho-substituted congener, 2,2′-chlorobiphenyl (CB), whereas, a non- ortho-substituted congener, 4,4′-CB, did not affect cell cycle progression. This interruption of cell cycle progression by 2,2′-CB and Aroclor 1242 was associated with a decreased expression of the cell cycle regulatory protein, cyclin D2, while expression was not affected by exposure to the non- ortho-substituted 4,4′-CB. These results suggest the preferential inhibition of LPS-induced splenocyte proliferation by ortho-substituted congeners is a result of a decreased expression of cyclin D2, which leads to an interruption in cell cycle progression. In addition, PCB mixtures with an increased percentage of chlorines in the ortho position following an environmentally occurring degradation process inhibited LPS-induced proliferation, interrupted cell cycle progression, and decreased cyclin D2 expression. This study provides evidence for a mechanism of action of the immunological effects of ortho-substituted individual congeners as well as environmentally relevant mixtures enriched in congeners with this substitution pattern.