Harp P

References (2)

Title : Potentiation of organophosphorus-induced delayed neurotoxicity following phenyl saligenin phosphate exposures in 2-, 5-, and 8-week- old chickens - Harp_1997_Fundam.Appl.Toxicol_37_64
Author(s) : Harp P , Tanaka D, Jr. , Pope CN
Ref : Fundamental & Applied Toxicology , 37 :64 , 1997
Abstract : Phenylmethylsulfonyl fluoride (PMSF), a nonneuropathic inhibitor of neurotoxic esterase (NTE), is a known potentiator of organophosphorus-induced delayed neurotoxicity (OPIDN). The ability of PMSF posttreatment (90 mg/kg, sc, 4 hr after the last PSP injection) to modify development of delayed neurotoxicity was examined in 2-, 5-, and 8-week-old White Leghorn chickens treated either one, two, or three times (doses separated by 24 hr) with the neuropathic OP compound phenyl saligenin phosphate (PSP, 5 mg/kg, sc). NTE activity was measured in the cervical spinal cord 4 hr after the last PSP treatment. Development of delayed neurotoxicity was measured over a 16-day postexposure period. All PSP-treated groups exhibited > 97% NTE inhibition regardless of age or number of OP treatments. Two-week-old birds did not develop clinical signs of neurotoxicity in response to either single or repeated OP treatment regimens nor following subsequent treatment with PMSF. Five-week-old birds were resistant to the clinical effects of a single PSP exposure and were minimally affected by repeated doses. PMSF posttreatment, however, significantly amplified the clinical effects of one, two, or three doses of PSP. A single exposure to PSP induced slight to moderate signs of delayed neurotoxicity in 8-week-old birds with more extensive neurotoxicity being noted following repeated dosing. As with 5-week-old birds, PMSF exacerbated the clinical signs of neurotoxicity when given after one, two, or three doses of PSP in 8-week-old birds. Axonal degeneration studies supported the clinical findings: PMSF posttreatment did not influence the degree of degeneration in 2-week-old chickens but resulted in more severe degeneration (relative to PSP only exposure) in cervical cords from both 5- and 8-week-old birds. The results indicate that PMSF does not alter the progression of delayed neurotoxicity in very young (2 weeks of age) chickens but potentiates PSP-induced delayed neurotoxicity in the presence of 0-3% residual NTE activity in older animals. We conclude that posttreatment with neuropathic or nonneuropathic NTE inhibitors, following virtually complete NTE inhibition by either single or repeated doses of a neuropathic agent in sensitive age groups, can modify both the clinical and morphological indices of delayed neurotoxicity. This study further supports the hypothesis that potentiation of OPIDN occurs through a mechanism unrelated to NTE.
ESTHER : Harp_1997_Fundam.Appl.Toxicol_37_64
PubMedSearch : Harp_1997_Fundam.Appl.Toxicol_37_64
PubMedID: 9193923

Title : Comparative developmental and maternal neurotoxicity following acute gestational exposure to chlorpyrifos in rats - Chanda_1995_J.Toxicol.Env.Health_44_189
Author(s) : Chanda SM , Harp P , Liu J , Pope CN
Ref : Journal of Toxicology & Environmental Health , 44 :189 , 1995
Abstract : Chlorpyrifos (CPF), an organophosphorus (OP) insecticide, exerts toxicity through inhibition of acetylcholinesterase (AChE). In the present study, pregnant Sprague-Dawley rats were given CPF (200 mg/kg, sc) as a single dose on gestation d 12 (GD12) and then sacrificed on either GD16, GD20, or postnatal d 3 (PND3) for measurement of maternal and developmental indicators of toxicity. While most CPF-treated rats exhibited no overt signs, a subset (4/28) showed moderate to severe signs of "cholinergic" toxicity at 2-3 d after treatment, and these rats were omitted from further studies. Extensive AChE inhibition (82-88%) was noted in maternal brain at all three time points following acute exposures. At GD16 and GD20, fetal brain AChE activity was inhibited 42-44%. While some degree of recovery in AChE activity was noted in pup brain by PND3, AChE activity was still inhibited (30%) in treated pups cross-fostered to control dams. In vitro inhibition of maternal and fetal (GD20) brain AChE activity by the active metabolite, chlorpyrifos oxon, suggested that the prenatal brain AChE activity was somewhat more sensitive (IC50 at 37.0 degrees C, 20 min: dam, 26.6 +/- 1.8 x 10(-9) M; fetus, 6.7 +/- 0.4 x 10(-9) M). Maternal brain muscarinic receptor binding was more extensively reduced (30-32%) at GD20 and PND3 as compared to the developing brain at GD20 (16%) and PND3 (11%). A simple postnatal reflex test (righting reflex) was transiently altered by CPF. The results suggest that CPF exposure to dams during gestation produces more extensive neurotoxicological effects in the dam relative to the developing fetus.
ESTHER : Chanda_1995_J.Toxicol.Env.Health_44_189
PubMedSearch : Chanda_1995_J.Toxicol.Env.Health_44_189
PubMedID: 7531776