How strong is the association between pesticide exposure and increased risk for Parkinson's disease and how do we translate this association into therapeutic strategies?

Last week the Department of Veteran's Affairs released new guidelines allowing veterans exposed to Agent Orange who suffer from Parkinson's disease to claim health benefits. Agent Orange is an herbicide used in the Vietnam War to defoliate Vietnamese jungles and has been linked to a multitude of health problems.

The new guidelines are based on a report from the Institute of Medicine of the National Academies regarding veterans and Agent Orange released earlier this year. The report details an association between the herbicide and PD based on 16 studies examining herbicide exposure in people with PD or PD-like symptoms. Because of the low number of studies in veterans, the committee strongly suggests further studies in Vietnam veterans and studies in animal models to investigate the relationship between Agent Orange and Parkinson's disease.

To reiterate the Research Question, what is known about the mechanism of these toxins leading to Parkinson's, and how should future studies be designed? What other factors contribute to PD risk from environmental toxins? And, aside from enabling veterans to claim health benefits for Parkinson's disease, how can this information be translated into therapeutic strategies?

Epidemiologic studies have consistently suggested that pesticide exposures heighten the risk of developing PD. Few studies have identified risk increases greater than 2-fold; occasionally risks are found to be greater for certain subgroups, e.g. by age or genetic variant. Fewer studies have identified specific pesticides.  The question of toxin specificity might be more relevant than the question of “how strong” an association is. Prevention of future PD cases requires a better understanding of the mechanisms, environmental and genetic, involved in disease etiology. Identification of specific pesticides that are contributing to the greatest number of PD cases and working to remove those from the market should be an important public health goal.

To identify specific pesticides, some issues must be addressed. Most human studies have relied on self-report and recall, bias-prone methods that make it challenging to pinpoint specific agents. Our UCLA team overcame this hurdle with a unique exposure assessment method that uses a geographic information system to combine historical addresses with land use maps and pesticide application records. Unlike any other state, the California Department of Pesticide Regulation collects these records allowing us to examine long term exposures to specific pesticides reaching the subjects due to drift or well water consumption (avenues of exposure difficult to capture by self-report).

Furthermore, we are especially excited to investigate how genetic factors may affect individuals’ susceptibility or resilience to environmental toxicants. For example, we recently confirmed a report by Kelada (2006) that DAT genetic variants increase the vulnerability to specific pesticides, as do functional variants of the PON1 gene. Therefore, a third important question is how and to what extent do genetic variants contribute to PD risk from pesticide or other environmental exposures? This question will only be adequately addressed, however, in studies that collect both very detailed environmental data as well as genetic samples and have sufficient sample size for statistical interaction testing.    

There has been a lot of excitement over the recent discoveries of PD-related genes, and for good reason.  However, there has not been as much excitement (unfortunately) about some of the more recent findings regarding pesticide exposure and PD (See recent works by Beate Ritz and Alexis Elbaz). For some reason the field seems to be split-that it must be genetics or it must be the environment.  This attitude is one that, in my opinion, has stifled research in the field.

We need to shift our focus towards the gene-environment interactions.  Geneticists need to start thinking about how the genotype alters susceptibility to environmental exposures, just as the toxicologists must consider how the response to the environmental exposures is dictated by an individual’s genetic makeup.  For the sake of discussion, if one views 10% of PD cases to be purely genetic and 10% to be purely environment, the remaining cases fall in between.  I consider this area to be the gene-environment continuum. We can debate where on the gene-environment continuum the majority of cases will be, but it is safe to assume that both genes and environment are making a contribution to disease pathogenesis.  We need to consider a systematic approach that evaluates genetic and environmental factors in an unbiased fashion. Teams of scientists that include geneticists, neurologists, epidemiologists, and toxicologists are going to be in a better position to identify how the combination of genes and environment contribute to the majority of cases.   It is not genes OR environment, it is genes AND environment.  Once we start to understand how the multiple factors interact, we will be able to design multipronged therapeutic strategies aimed at slowing progression and restoring function.

3,4-dihydroxyphenylacetaldehyde (DOPAL) is the monoamine oxidase (MAO) metabolite of dopamine (DA). DOPAL is is present at physiological relevant levels in humand brain (Kristal et al., 2001) and is toxic to DA neurons in vitro (Kristal et al., 2001) and in vivo (Burke et al., 2003). DOPAL injections into rat substantia nigra (SN) produces an animal model of Parkinson disease (PD) (Burket et al., 2009). DOPAL is metabolised to 3,4-dihydroxyphenylacetaldehyde (DOPAC) by SN cytosolic aldehyde dehydorgenase 1A1 (ALDH1A1) and mitochondrial ALDH2 (Marchitti et al., 2007) with nicotinamide adenine dinucleotide (NAD) as  cofactor.

Pesticides which inhibit complex I, like rotenone, decrease NAD levels and increase DOPAL levels in vitro (Lamensdorf et al., 2000). In vivo, chronic rotenone injection produces a precise model of PD in rats (Betarbet et al., 2000).  Alternately, other pesticides trigger oxidative stress and the the formation of the  lipid  peroxidation products 4-hydroxy-2-nonenal (4HNE) and malondialdehyde (MDA), potent inhibitors of ALDH (McCormack et al., 2005; Florang et al., 2006; Jinsmaa et al., 2009). Both 4HNE and MDA increase DOPAL levles in vitro [8,9].

Thus DOPAL  provides a key chemical link between pesticides and PD.

Burke W.J. et al. Neurology 72: 342A, 2009.