An aryl hydrocarbon receptor independent mechanism of JP-8 jet fuel immunotoxicity in Ah-responsive and Ah-nonresponsive mice.
JP-8 jet fuel is handled extensively by personnel in the military and commercial airlines, despite the paucity of information regarding its potential human health effects. JP-8 is a complex mixture primarily consisting of kerosene plus aliphatic and aromatic hydrocarbons. Recent reports indicate that acute JP-8 exposure via inhalation or dermal routes can overtly and persistently impair immune function in mice. Data from preliminary studies in this laboratory assessing the immunotoxicity of JP-8 indicated that oral JP-8 exposure caused an increase in liver weight, a decrease in thymus weight, and a decrease in the PFC response. As these results were similar to classic effects elicited by TCDD, a strong AhR ligand, it was hypothesized that JP-8 may exert immunosuppression via a similar mechanism. To test this hypothesis, an Ah-responsive mouse strain (B6C3F1) and a classically non-responsive mouse strain (DBA/2) bearing a lower affinity AhR were gavaged with JP-8 for 7 days. The results suggest that both mouse strains were equally sensitive to JP-8's toxicity at several endpoints including thymus weight and cellularity, liver weight, and specific IgM antibody responses. Furthermore, JP-8 did not induce CYP1A1 or promote down regulation of the AhR when evaluated by Western blot in either B6C3F1 or DBA/2 mice. In vitro studies corroborated these findings as JP-8 did not induce CYP1A1, promote down regulation of the AhR, or activate an XRE-driven reporter gene in murine Hepa-1 cells. These results suggest that JP-8 may exert its toxicity via an AhR-independent mechanism.
Dudley
A C
AC
Department of Environmental Studies, The Medical University of South Carolina, Charleston, South Carolina, USA.
Peden-Adams
M M
MM
EuDaly
J
J
Pollenz
R S
RS
Keil
D E
DE
D000284:Administration, Oral; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D015153:Blotting, Western; D002452:Cell Count; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D017930:Genes, Reporter / Q000187:drug effects; D006462:Hemolytic Plaque Technique; D006838:Hydrocarbons / Q000008:administration & dosage / Q000633:toxicity*; D007109:Immunity / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics*; D013950:Thymus Gland / Q000187:drug effects / Q000473:pathology
D006838:Hydrocarbons; C098607:JP8 aviation fuel; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D019363:Cytochrome P-450 CYP1A1