Fitzmaurice AG, Rhodes SL, Cockburn M, Ritz B, Bronstein JM. Aldehyde dehydrogenase variation enhances effect of pesticides associated with Parkinson disease. Neurology. 2014;82(5):419-26.
Combination of population-based case control study data and a novel ex vivo assay to assess inhibition of a key metabolic pathway of dopamine, aldehyde dehydrogenase 2, by individual pesticides.
The Parkinson’s Environment Gene (PEG) study participants, including 350 confirmed cases of Parkinson's disease (PD) in Central California valley. Control group included 518 gender- and age-matched members of the same communities with genetic data available, and 289 without genetic information.
“Common variants in the mitochondrial ALDH2 gene were genotyped to assess effect measure modification (statistical interaction) of the pesticide effects by genetic variation.”
Many of the pesticides assayed ex vivo inhibited ALDH2, including “dithiocarbamates … (eg, maneb, ziram), 2 imidazoles (benomyl, triflumizole), 2 dicarboxymides (captan, folpet), and 1 organochlorine (dieldrin).” These pesticides were associated with 2- to 6-fold increases in PD risk. Those with a genetic variation of ALDH2 had an exacerbated risk when exposed to ALDH-inhibiting pesticides. Fifteen pesticides screened through ex vivo assay did not inhibit ALDH2, and these were not associated with greater risk of PD.
Pesticides have been implicated in neurodegenerative diseases such as Alzheimer’s disease and PD for decades.1,2 Epidemiological data consistently show that there are a higher rates of PD associated with pesticide exposures in farm workers and rural dwellers.3,4 While association is not disputed, assumptions regarding causation require a better understanding of which pesticides are suspect and who is most susceptible to the neurotoxicity of these agents. The PEG study is an ongoing study that seeks to answer these most practical questions.
The PEG study is unique in that it does not rely on participant recall for pesticide exposure assessment. Instead, exposures are assessed using the California Pesticide Use Reporting Database, which began in 1974 and includes the type of compound, quantity, and location. This, combined with the Geographic Land use system of maps, allows a historical exposure assessment based on residency and occupation site for all study participants.
There are many proposed mechanisms of PD pathogenesis, all of them resulting in neurotoxicity to the substantia nigra and the accumulation of Lewy bodies, which are aggregations of the neuronal protein alpha syn. Interestingly, dopamine itself and its metabolites are implicated in the aggregation of the most toxic forms of alpha syn.5 One metabolite in particular 3,4-dihydroxyphenylacetaldehyde (DOPAL), is highly toxic to dopaminergic cells.6 Aldehyde dehydrogenase 2 (ALDH2) is the enzyme that degrades DOPAL, so inhibiting this enzyme leads to higher levels of DOPAL accumulation and greater neurotoxicity.7 As the current study shows, many pesticides are able to inhibit ALDH2. Such inhibition, coupled with a genetic alteration in ALDH2 efficiency, appears to amplify the neurotoxic effects and increase risk of developing PD.
How one metabolizes pesticides may be more important than exposure itself. Many other gene mutations have been found to only be relevant when both the genetic variation and exposure to pesticides is present. These include alterations in cytochrome P450 pathway 2D6,8 nitric oxide synthase I,9 dopamine transporter alleles,10 and pathways specific to given pesticide degradation such as paraoxonase I11 (organophosphates) and dinucleotide repeat sequence12 (paraquat). Of course, these are just the variations we know of to date. Given that only 5% of PD is strongly genetically determined (familial), these variations in metabolic pathways may explain causation for at least some of the 95% of “sporadic” cases of PD.
One important thing to note from the PEG study is that recent exposures to pesticides, after 1990, is not associated with increased risk. This may be due to taking better precautionary measures in the workplace as well as at home. It may also be an artifact of the long evolution of toxic neurodegeneration. One hopes it is due to stopping the use of the most toxic ALDH2 inhibiting agent tested, dieldrin. In the present study exposure to dieldrin, which is currently banned in all developed countries, raised the risk of developing PD 8-fold in those with exposures at work and home. Let’s hope that the more light that is shed on direct causation, the more such highly toxic compounds will be identified and removed completely from use. Given their persistence in the soil, it is a good place to start.
Pesticides found to be inhibitors of ALHD2 in this study:
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