DOPAMINERGIC TOXICITY OF ATRAZINE--INFLUENCE OF AGE

Mississippi State University, Mississippi State MS

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): The research proposed here will explore the possibilities (i) that both very young and aged mice are more susceptible to atrazine neurotoxicity than their adult counterparts, (ii) that short-term exposure to atrazine during adolescence will potentiate the age-related DA loss, as well as potentiate the toxicity of a typical basal ganglia neurotoxicant such as 1-methyl-4-phenyl-1, 2, 3, 4-tetrahydropyridine (MPTP), and (iii) that a sub-chronic or chronic low level of exposure to atrazine will either be neurotoxic on its own, or it will potentiate the toxicity MPTP. It is hypothesized that short-term exposure to atrazine of adolescent and aged, but nor adult mice, would result in dopaminergic neurotoxicity that will persist, and that only mice exposed to atrazine during adolescence, but not during adulthood, will have dopaminergic loss in old age that is greater than that associated 14th the normal aging process. Moreover, it is hypothesized that a sub-chronic or chronic, low level of exposure to atrazine will not be neurotoxic on its own, but it will potentiate the effects of the basal ganglia neurotoxicant MPTP. To address this hypothesis, male C57BL/6 mice, l, 3, and 18 months of age, will be exposed to various dosages of atrazine for either short-term (14 days) or long-term (13 and 26 weeks; 1 and 3 month old mice only) and the degree of dopaminergic neurodegeneration and microglia activation will be assessed after termination of atrazine exposure. Additionally, to gain a mechanistic insight on atrazine-induced basal ganglia neurotoxicity, in vitro experiments with striatal slices and mixed mesencephalic cultures will be performed. The specific aims of this grant application are: Specific Aim 1: To assess dopaminergic neurotoxicity of acute exposure to atrazine in adolescent, adult, and aged mice. The degree of neuronal loss and microglial cell activation will be examined. Male C57BL/6 mice, aged 1, 3, and 18 months, will be treated with different dosages of atrazine for 14 days. The level of dopaminergic/other neuronal cell loss, as well as regional (in striatum and substantia nigra) microglial cell activation, will be assessed at various time points (up to 49 days) after termination of atrazine exposure. An additional subset of mice will be challenged with MPTP to assess the ability of atrazine to modify MPTP toxicity. Specific Aim 2: To assess the long-term effects of an earlier short-term exposure to atrazine during adolescence and adulthood on the age-related dopaminergic neuronal loss and, possible microglial activation in old age. Male C57BL/6 mice, 1 and 3 months of age, will be treated with different dosages of atrazine for 14 days and examined for a degree of dopaminergic neuronal cell loss and associated decline in striatal DA, as well as regional microglial cell activation when the animals become 18 months old. As in Specific Aim 1, an additional subset of mice will be challenged with MPTP to assess the ability of atrazine to exacerbate MPTP toxicity. Specific Aim 3: To assess dopaminergic neurotoxicity in old age of chronic, low-level exposure to atrazine during adolescence and adulthood, as well as to assess the influence of previous chronic, lowlevel exposure to atrazine on subsequent response to the dopaminergic neurotoxicant, MPTP. Male C57BL/6 mice, 1 and 3 months of age, will be treated with different dosages of atrazine for either 13 or 26 weeks and examined for the degree of dopaminergic neuronal cell loss and associated decline in striatal DA, as well as regional microglial cell activation at ages of 12 and 18 months. As in Specific Aims 1 and 2, an additional subset of mice will be challenged with MPTP to assess the ability of atrazine to exacerbate MPTP toxicity. Specific Aim 4: To assess dopaminergic neurotoxicity of atrazine in vitro, including potential mechanism(s) and possible microglial involvement, by using striatal slices and mesencephalic primary cultures. Striatal slices and mesencephalic primary cultures will be exposed to a dose range of atrazine and dopaminergic toxicity will be assessed in the presence of varying degrees of microglial activation with lipopolysaccharide (LPS). By using various pharmacological manipulations, direct-only vs. directplus-indirect effects of atrazine and the relative contribution of specific factors produced by microglia to atrazine-induced dopaminergic cell toxicity (if present) will be determined.