Production of complement component C3 in vivo following 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure.
Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been shown to decrease serum complement C3 levels in female B6C3F1 mice but failed to alter C3 production when added in vitro to either hepatoma cells (both human and mouse hepatoma cells) or mouse primary hepatocytes (Lin and White, 1993a). It has also been demonstrated that mouse liver intracellular C3 levels were not affected following TCDD exposure in vivo, while serum C3 levels were suppressed (Lin and White, 1993b). Therefore, further studies were undertaken to investigate the mechanism by which TCDD modulates newly synthesized serum C3 in vivo. Mouse serum C3 was depleted by an intravenous injection of 50 anti-complement units (ACU)/kg cobra venom factor (CVF). This dose of CVF depleted serum C3 levels to 9% of control at 24 h after treatment. Subsequently, serum C3 levels returned to 19% and 75% of the control level on d 3 and d 5. The recovery of serum C3 was then monitored following an acute oral exposure to 20 micrograms/kg TCDD. In mice exposed to both TCDD and CVF, serum C3 levels reached 15% and 69% of control on d 3 and d 5 after treatment; these results were not significantly different from those of mice treated with CVF alone. Furthermore, when the radiolabeled amino acid [3H]leucine was injected intravenously into either vehicle- or TCDD-treated mice, the incorporation of this labeled precursor into both C3 and other secreted plasma proteins was not inhibited by TCDD. These results demonstrated that TCDD did not decrease newly synthesized C3 in vivo. These studies provide additional support for the concept that TCDD does not act directly on hepatocytes to suppress C3 production. The lower serum C3 levels observed in vivo following TCDD exposure is not the result of a decrease in C3 production by hepatocytes.
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0613.
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D000284:Administration, Oral; D000818:Animals; D003176:Complement C3 / Q000096:biosynthesis*; D004546:Elapid Venoms; D005260:Female; D007930:Leucine; D008099:Liver / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000633:toxicity*; D013047:Specific Pathogen-Free Organisms
D003176:Complement C3; D004546:Elapid Venoms; D000072317:Polychlorinated Dibenzodioxins; C016310:cobra venom factor; D007930:Leucine