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EXAMINATION OF THE EFFECTS OF CHLORPYRIFOS ON DEVELOPMENTAL PROCESSES: EVALUATION OF BIOCHEMICAL, MORPHOLOGICAL, AND BEHAVIORAL INDICES OF DEVELOPMENTAL NEUROTOXICITY.
Citation:
Barone, S, T. L. Lassiter, L. D. White, V. Moser, AND S. Padilla. EXAMINATION OF THE EFFECTS OF CHLORPYRIFOS ON DEVELOPMENTAL PROCESSES: EVALUATION OF BIOCHEMICAL, MORPHOLOGICAL, AND BEHAVIORAL INDICES OF DEVELOPMENTAL NEUROTOXICITY. Presented at Teratology, Scottsdale, AZ, 6/22/2002.
Description:
Until recently, the organophosphate pesticide, chlorpyrifos [CPF; O,O'diethyl O-3,5,6-trichloro-2-pyridyl) phosphorothionate] was one of the highest volume use pesticides in a non agricultural setting. The principal reason for restriction of use of this pesticide has been concern about children's risk. The aim of this paper is to outline the mechanism and modes of action by which developmental neurotoxicity can occur following gestational exposure with this demonstration compound. This paper outlines age-related sensitivity in metabolism of this pesticide and qualitative factors that relate to increased susceptibility of the developing brain. Pregnant Long-Evans rats were dosed daily (p.o.) with CPF (0, 1, 3, 5, 7, and 10 mg/kg/d) in corn oil on gestational days 14-18. Fetuses were examined at 2, 5, 10, and 24 hours after the last dose. In the fetal brain total cholinesterase, acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) were 70, 75, and 53 % of control activity levels 5 hours after the last 7 mg/kg/d dose of chlorpyrifos. In previous studies the time of peak brain AChE inhibition in mom and fetus was determined to be at 5 hours after the last dose. Fetal brain AChE inhibition at the time of peak effect was not significant at the 1 or 3 mg/kg, while observed BuChE was inhibited at all doses of CPF except 1 mg/kg/d. Exposure-related changes in fetal brain neurotrophic factors levels and apoptosis were observed. There was a decrease in BDNF and NT-3 IR in the brains of CPF treated fetuses. These CPF-related changes in NTF-IR are consistent with quantitative changes in whole brain BDNF and NT-3 levels determined by enzyme-linked immunoabsobent assays (ELISA)s. Immunohistochemistry demonstrated that these changes in NTF levels determined in ELISAs were primarily limited to proliferative zones of the forebrain. Results from cell death ELISA showed the highest level of oligonucleosomal cleavage at the 7 mg/kg/day dosage at 5 hours after the last dose of CPF. Terminal transferase dUTP nick end-labeling (TUNEL) assays of fetal brains showed increased numbers of apoptotic cells in the proliferative zones of the striatum, hippocampus and cortical plate of the neocortex. The altered pattern of apoptosis in the fetal brains of CPF-exposed rats were reciprocal to the changes in BDNF and NT-3 IR in proliferative and post migratory zones. This observed increase in apoptosis could be due to the demonstrated changes in neurotrophin levels. Further, these changes in regional levels of neurotrophins and apoptosis with CPF exposure suggest possible alterations in cell number and function that could persist in the adult nervous system. Fetal brain sections stained with cresyl violet, for neuropathological assessments showed overt pathology was present in the neocortex. The lesions observed included alterations in vasculature, disorganized migratory waves, ectopic cells, neuropathological holes, and qualitative thinning of the ventricular zone and cortical plate. These morphological effects were dose-related and observed at all doses tested. Stereological quantification of the volume of the ventricular zone, subventricular zone, and cortical plate in the fetal neocortex did not show treatment-related changes. We conclude that gestational exposure to CPF not only inhibits cholinesterase activity in the fetal brain, but also causes neuropathological changes in the fetal neocortex at doses below the level of detectable brain cholinesterase inhibition in the fetus and that many of these neuropathological changes resolve with time after cessation of dosing. There are however persistent changes in postnatal regional neurotrophic factor levels and alteration in cognitive function in a Morris water maze task performed in adult offspring. This abstract does not reflect EPA policy.