The Acute Neurotoxicity of Benzo (a)pyrene in F-344 Rats (2001). C. R. Saunders, Mehary Medical College
There are only a few studies examining the potential neurotoxic effects of polycylic aromatic hydrocarbons (PAHs). In this study, we examined the neurobehavioral effects of single oral doses of B(a)P, a prototype agent of this family of compounds, on motor activity and the functional observational battery (FOB) in eight-week-old male and female F-344 rats. Single oral doses of B(a)P (12.5-200 mg/kg) were administered to rats by gavage. Dose and time-dependent decreases in locomotor activity (up to 70%) following B(a)P administration were observed in both sexes on days 1and 2, with recovery to control levels by day 3 in all B(a)P exposed animals. Results of the functional observational battery (FOB) revealed significant (P<0.001) neuromuscular and autonomic deficits and decreased responses to sensorimotor stimuli. Behavioral effects peaked at 6 hr in all FOB endpoints but were reversible by 72 hrs. Significant (P<0.001) gender differences were noted in behavioral endpoints with males showing greater sensitivity to B(a)P dosing. The 12.5 mg/kg dose of B(a)P was determined to be the no-adverse effect-level in both sexes.
Toxicokinetic studies were conducted to evaluate the disposition of B(a)P in the central nervous system and plasma. Plasma and brain tissue (cortex and cerebellum) were analyzed for parent B(a)P and its metabolites by HPLC with fluorescence detection. B(a)P metabolites were detected in the plasma and brain in B(a)P exposed males within 2 hrs, reached maximum concentrations at 6 hr followed by a gradual decline at 24 and 48 hrs. Only trace levels of parent B(a)P and its metabolites were detected at 96 hrs.
The effects of B(a)P (100 and 200 mg/kg) on dopamine levels in the striatum were examined at 24 and 48 hrs post treatment in male rats by high performance liquid chromatography to determine the neurochemical mechanisms of B(a)P induced behavioral toxicity. ANOVA revealed significant (p<0.001) dose dependent decreases in striatal dopamine content in B(a)P exposed males.
These findings suggest that metabolism may modulate the neurobehavioral toxicity of B(a)P. Decreased levels of striatal dopamine may contribute to motor activity deficits. Dose-response and time course data from our studies may be potentially useful in the risk assessment process filling major gaps regarding the acute neurotoxicity of PAHs.
This research was supported by grants U50-ATU398948 and T32-HLO7809.
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