Tumor necrosis factor is involved in chlorpyrifos--induced changes in core temperature in the female rat

Chlorpyrifos (CHP), an OP-based pesticide, induces hypothermia in the rat followed by a fever that persists for several days. The cytokine, tumor necrosis factor-alpha (TNF), is induced by lipopolysaccharide (LPS) and released during fever and has both pyrogenic and cryogenic (i.e. antipyretic) properties. Administering antibodies to TNF (anti-TNF) is known to disrupt fever from infection. Thus, the purpose of this study was to examine whether anti-TNF also disrupts CHP-induced changes in body temperature of the female Long-Evans rat. A positive effect would suggest a role of TNF in the etiology of OP toxicity. In study one, rats were given either saline or anti-TNF (50,000 units, i.p.). Three hours later, animals were given corn oil (CO) or 25 mg/kg CHP by oral gavage in the morning. In study two, rats were given anti-TNF followed by CO or 10 mg/kg CHP in the afternoon. Core temperature and motor activity were monitored continuously by telemetry. In study one, anti-TNF (50,000 units) had no effect on the hypothermic response to 25 mg/kg CHP. However, anti-TNF treated animals maintained higher fevers 3 days (48-96 h post-injection) after CHP treatment. In study two, anti-TNF attenuated the hypothermic response induced by 10 mg/kg CHP but had no effect on the magnitude of the delayed fever. Overall, 25 mg/kg CHP elicited a longer period of hypothermia and delayed fever compared to 10 mg/kg CHP. Anti-TNF pretreatment attenuated the hypothermic response at the lower CHP dose and exacerbated the fever at the higher CHP dose. Anti-TNF also attenuated the hypothermic effect of high doses of LPS and exacerbated LPS-induced fever. These data indicate that endogenously produced TNF is involved in the etiology of CHP mediated hypothermia and fever.