Parkinson's Disease and Residential Exposure to Maneb and Paraquat From Agricultural Applications in the Central Valley of California

Department of Environmental Health Sciences, University of California, Berkeley, 94720-7360, USA.
American journal of epidemiology (Impact Factor: 5.23). 04/2009; 169(8):919-26. DOI: 10.1093/aje/kwp006
Source: PubMed


Evidence from animal and cell models suggests that pesticides cause a neurodegenerative process leading to Parkinson's disease
(PD). Human data are insufficient to support this claim for any specific pesticide, largely because of challenges in exposure
assessment. The authors developed and validated an exposure assessment tool based on geographic information systems that integrated
information from California Pesticide Use Reports and land-use maps to estimate historical exposure to agricultural pesticides
in the residential environment. In 1998–2007, the authors enrolled 368 incident PD cases and 341 population controls from
the Central Valley of California in a case-control study. They generated estimates for maneb and paraquat exposures incurred
between 1974 and 1999. Exposure to both pesticides within 500 m of the home increased PD risk by 75% (95% confidence interval
(CI): 1.13, 2.73). Persons aged ≤60 years at the time of diagnosis were at much higher risk when exposed to either maneb or
paraquat alone (odds ratio = 2.27, 95% CI: 0.91, 5.70) or to both pesticides in combination (odds ratio = 4.17, 95% CI: 1.15,
15.16) in 1974–1989. This study provides evidence that exposure to a combination of maneb and paraquat increases PD risk,
particularly in younger subjects and/or when exposure occurs at younger ages.

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Available from: Sadie Costello
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    • "well established (reviewed in Henchcliffe and Beal 2008), increasing evidence suggests a role for gene–environmental interactions contributing to the sporadic form of the disease, and gene regulatory networks are being unraveled (Kumar Singh et al. 2014; Krug et al. 2014; Fujita et al. 2014; Todorovic et al. 2014; Maertens et al. 2015; Lee and Cannon 2015; Rahnenführer and Leist 2015). Exposure to pesticides such as rotenone may be associated with increased risk of PD (Ascherio et al. 2006; Costello et al. 2009; Wang et al. 2011; Tanner et al. 2011). Mitochondrial dysfunctions (e.g., toxicant-induced mitochondrial complex I inhibition) are believed to be central in the pathophysiology of PD (reviewed in Franco-Iborra et al. 2015); however, it is not clear whether this is a primary or secondary event in PD pathogenesis. "
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    ABSTRACT: Several shortcomings of current Parkinson's disease (PD) models limit progress in identification of environmental contributions to disease pathogenesis. The conditionally immortalized cell line LUHMES promises to make human dopaminergic neuronal cultures more easily available, but these cells are difficult to culture for extended periods of time. We overcame this problem by culturing them in 3D with minor medium modifications. The 3D neuronal aggregates allowed penetration by small molecules and sufficient oxygen and nutrient supply for survival of the innermost cells. Using confocal microscopy, gene expression, and flow cytometry, we characterized the 3D model and observed a highly reproducible differentiation process. Visualization and quantification of neurites in aggregates was achieved by adding 2 % red fluorescent protein-transfected LUHMES cells. The mitochondrial toxicants and established experimental PD agents, rotenone and MPP(+), perturbed genes involved in one-carbon metabolism and transsulfuration pathways (ASS1, CTH, and SHTM2) as in 2D cultures. We showed, for the first time in LUHMES, down-regulation of mir-7, a miRNA known to target alpha-synuclein and to be involved in PD. This was observed as early as 12 h after rotenone exposure, when pro-apoptotic mir-16 and rotenone-sensitive mir-210 were not yet significantly perturbed. Finally, washout experiments demonstrated that withdrawal of rotenone led to counter-regulation of mir-7 and ASS1, CTH, and SHTM2 genes. This suggests a possible role of these genes in direct cellular response to the toxicant, and the model appears to be suitable to address the processes of resilience and recovery in neurotoxicology and Parkinson's disease in future studies.
    Full-text · Article · Dec 2015 · Archives of Toxicology
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    • "Several environmental factors have been proposed to increase the risk of PD development; epidemiological studies suggest a significant role played by pesticides, including paraquat (PQ) and maneb (MB) as risk factors in the aging-related diseases (Costello et al., 2009). "
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    ABSTRACT: Paraquat (PQ) and maneb (MB) are able to induce neurotoxic effects by promoting α-synuclein (α-syn) aggregates and altering tyrosine hydroxylase (TH), thus increasing the risk of Parkinson's disease (PD). These pesticides promote neurotoxic effects also by affecting proteasome function that normally regulate protein turnover. We investigated the effects of the two pesticides exposure on multiple targets involved in PD, using SH-SY5Y cells. First, we evaluated TH and α-syn protein levels following PQ and MB cell exposure and a significant increase of these protein levels was observed. Subsequently, since a relationship between ubiquitin/proteasome and opioid receptors has been proposed, the effects of pesticides on their gene expression have been investigated. A decrease of β1 and Rpt3 proteasome subunit mRNA levels, together with the μ and δ opioid receptor down-regulation, was detected. The reported alterations, here simultaneously observed, help to clarify the involvement of multiple biological markers implicated in PD, often separately evaluated.
    Full-text · Article · Oct 2015
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    • "This association supports the usefulness of exposure indices as a proxy for pesticide exposure in our study population. Similar indices have also been used in previous studies to assess pesticide exposure (Costello et al., 2009; Meyer et al., 2006; Thomas et al., 2010). A recent study in a French birth control has shown a positive association between urinary "
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    ABSTRACT: Background: Childrens exposure to neurotoxic compounds poses a major problem to public health because of their actively developing brain that makes them highly vulnerable. However, limited information is available on neuropsychological effects in children associated with pre- and postnatal exposures to pesticides. Objective: To evaluate the association between current and pre- and postnatal exposures to pesticides and their effects on neurodevelopment in children aged 6-11 years living in agricultural communities fromSouth-Eastern Spain. Methods: An ambispective study was conducted on 305 children aged 6-11 years randomly selected from public schools of the study area. Current exposure to organophosphate pesticides was assessed measuring children's urinary levels of dialkylphosphates (DAPs). Both prenatal and postnatal residential exposure to pesticides was estimated by developing a geographical information system (GIS) technology-based index that integrated distance-weighted measure of agricultural surface, time-series of crop areas per municipality and year, and land-use maps. Neuropsychological performance was evaluated with the Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV). The association of pre- and postnatal and current pesticide exposure withWISC-IV scale scores was assessed using multivariate linear regression models and generalized estimating equation (GEE) models, respectively. Results: Greater urinary DAP levels were associated with a poorer performance on intelligence quotient and verbal comprehension domain, with effects being more prominent in boys than in girls. The influence of an increase in 10 ha per year in crop surface around the child's residence during the postnatal periodwas associated with decreased intelligence quotient, processing speed and verbal comprehension scores. As regards prenatal exposure to pesticides, a poor processing speed performance was observed. These effects were also more prominent in boys than in girls. Conclusions: Our results suggest that postnatal exposure to pesticides can negatively affect children's neuropsychological performance. Prenatal exposure was weakly associated to neurodevelopment impairment.
    Full-text · Article · Oct 2015 · Environment international
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