Host Susceptibility to Environmental Toxicants

Open Access
Author:
Alam, Gelareh
Graduate Program:
Biobehavioral Health
Degree:
Doctor of Philosophy
Document Type:
Dissertation
Date of Defense:
May 01, 2015
Committee Members:
  • Byron C Jones, Dissertation Advisor
  • David John Vandenbergh, Committee Chair
  • Sonia Angele Cavigelli, Committee Member
  • Shedra Amy Snipes, Committee Member
  • Xuemei Huang, Special Member
Keywords:
  • Host susceptibility
  • MPTP
  • Paraquat
  • Parkinson's Disease
  • Environmental Toxicants
Abstract:
Heavy metals, pesticides and herbicides are suspected risk factors for neurological disorders including Parkinson’s disease (PD). Nevertheless, their role is not clear- cut, as there are inconsistencies in epidemiological and preclinical research. One reason may be related to individual differences in susceptibility, differences that can be traced to the genetic constitution of those humans and animals exposed. Taking into account the role of host susceptibility and individual differences in the study of complex traits such as pesticide toxicity will result in better understanding the etiology and pathways involved in the development of complex neurological disorders such as Parkinson’s Disease (PD). Newer epidemiological and animal methods address the role of genes, the environment and their interaction as key. Increased sensitivity to paraquat toxicity, a broadly used herbicide, in C57B6 mice compared to D2 is an example that highlights the importance of genetic constitution and gene-environment interaction. In this thesis, we report a broad response variation to MPTP neurotoxicity in 9-10 strains of BXD recombinant male and female mice. MPTP is a dopaminergic neurotoxin that induces parkinsonism symptoms in humans and animals who have been systemically exposed to it. MPTP neurotoxicity results in a significant reduction of dopamine (DA) concentration in the striatum in humans, primates and mice. C57B6 Mice exposed to a single injection of 30mg/kg MPTP show a 40-50% reduction of the striatal DA concentration. Using genetic reference families such as BXD RI mice with known genetic constitution, allows us to investigate the importance of host susceptibility in response to neurotoxicants including, but not limited to MPTP. Striatal dopamine (DA) and its metabolites, DOPAC and HVA, and serotonin and its metabolite, 5-HIAAA, were analyzed by HPLC. DA turnover was assessed using DOPAC/DA and HVA/DA ratios. Striatal tyrosine hydroxylase (TH), glial fibrilary acidic protein (GFAP), and iron content in ventral midbrain were quantified. All dopamine measures, as well as TH and GFAP, demonstrated wide, genotype-dependent differences in response to MPTP in both sexes. A significant correlation between DA related phenotypes with the exception of DOPAC was observed between males and females, indicating the involvement of iii multiple factors in dopaminergic neurotoxicity and probably neurological disorders such as PD. Moreover, our data show that the association between MPP+ levels, the active metabolite of MPTP, and the striatal dopamine compromise caused by MPTP treatment is weak and not statistically significant. The results of this thesis support the complex nature of host susceptibility to neurotoxicants in which multiple genes and possibly multiple environmental factors are involved. This systemic approach to the study of environmental neurotoxicants in genetic reference populations of mice is likely to elucidate genetic factors underlying individual differences in developing neurodegenerative diseases such as PD.