Glucose feeding exacerbates parathion-induced neurotoxicity.

Excessive dietary intake of sugars could alter various biotransformation processes and the pharmacological and toxicological properties of numerous xenobiotics. In the present study, the effects of glucose supplementation were examined on the neurotoxicity of the organophosphorus (OP) pesticide parathion (PS) and its active metabolite, paraoxon (PO), a potent inhibitor of acetylcholinesterase (AChE). Rats (n = 6-12/treatment group) were given free access to tap water or 15% glucose (w/v) in tap water beginning 7 d prior to OP toxicant exposure. Food, caloric intake, and body weight were measured daily. Animals were challenged with either PS (4.5, 9, or 18 mg/kg, sc) or PO (0.3 0.5, or 0.7 mg/kg, sc) and clinical signs of neurotoxicity (i.e., autonomic dysfunction, involuntary movements) were recorded daily for the following 13 d. Glucose feeding was associated with a dramatic drop (approximately 50%) in feed intake and an increase (approximately 20% in total caloric consumption over the 7 d prior to OP exposure. Functional toxicity associated with PS exposure was increased in glucose-fed (GF) rats, but the glucose diet had no apparent effect on clinical signs of toxicity following PO treatment. Glucose feeding increased the magnitude of AChE inhibition in the frontal cortex and plasma at lower dosages (i.e., 4.5 and 9 mg/kg) 3 d following PS treatment. Time-course studies (3, 7, and 11 d after PS exposure, 18 mg/kg, sc) indicated significantly greater brain and plasma AChE inhibition in glucose-fed animals at later time points. In contrast, glucose feeding had no effect on the degree of AChE inhibition following PO exposure. Neither liver microsomal oxidative desulfuration of PS, nor liver or plasma paraoxonase, nor liver or plasma carboxylesterase activities were measurably affected by glucose feeding. Downregulation of muscarinic receptors 7 d after PS exposure (18 mg/kg, sc) was more extensive in GF rats. It is postulated that excessiveglucose consumption decreases the intake of other dietary components, in particular amino acids, limiting the de novo synthesis of AChE and consequent recovery of synaptic transmission. Due to the shorter duration of inhibition following PO exposure, sponta neous reactivation of AChE may be more important than de novo protein synthesis in recovery of function, and thus with the effects of glucose feeding on its toxicity. Individuals that derive a large proportion of their calories from sugars may be at higher risk of acute toxicity from organophosphorus pesticides such as PS.

Age-related effects of chlorpyrifos on acetylcholine release in rat brain.

Chlorpyrifos (CPF) is an organophosphorus insecticide that elicits toxicity through inhibition of acetylcholinesterase (AChE). Young animals are markedly more sensitive than adults to the acute toxicity of CPF. We evaluated acetylcholine (ACh) release and its muscarinic receptor-mediated regulation (i.e. muscarinic autoreceptor function, MAF) during maturation as a possible contributing factor to age-related differences in sensitivity. Cortical and striatal slices were prelabeled with [3H]choline chloride, superfused in the presence or absence of the anticholinesterase physostigmine (PHY, 20 microM) and stimulated twice (S1 and S2) with a high concentration of potassium chloride (20 mM). Depolarization-stimulated ACh release (DSAR) was lowest in neonatal, intermediate in juvenile and markedly higher in adult tissues. MAF was not detectable in tissues from neonatal rats but was present in juvenile and adult tissues. ACh release and MAF were studied at 4, 24 and 96 h following oral exposure to CPF (0, 0.5 or 1 x LD10). In general, 40-60% and 80-90% maximal AChE inhibition followed exposure to the respective 0.5 and 1 x LD10 dosages. DSAR was decreased in neonatal cortex 1 day after LD10 exposure but increased in juvenile striatum 1 day after LD10 treatment. In adults, DSAR was reduced at 4 and 24 h after exposure, but increased 96 h after CPF exposure. In juveniles, MAF was reduced in both brain regions at 24 h after 0.5LD10 exposure and at 24 and 96 h after LD10 exposure in cortex. A later reduction in MAF was noted in adult tissues (i.e. only at 96 h after LD10 treatment). Together, the results suggest that ACh release dynamics in brain vary markedly during postnatal maturation and that acute CPF exposure can alter ACh release in an age-related manner. The functional status of presynaptic processes regulating neurotransmitter release may contribute to age-related neurotoxicity elicited by high-dose exposures to chlorpyrifos.