Genes and Pesticides Interact to Increase PD Risk
A study published in the June issue of the Archives of Neurology found that men with certain variations in a gene called ABCB1 who were exposed to high levels of toxic pesticides were three and a half times more likely to develop Parkinson's disease than those with the normal version of the gene. The pesticides that were assessed in the study belong to a class called organochlorines, which includes DDT.
The Michael J. Fox Foundation spoke with Jason R. Richardson MS, PhD of the Robert Wood Johnson Medical School and Environmental and Occupational Health Sciences Institute to gain a better understanding of what the study results mean for people living with PD and the next steps for this area of research.
MJFF: Let's start by discussing why it's important to study the interaction between genetic and environmental factors in Parkinson's disease research.
JR: For Parkinson's disease, in most cases, neither a specific genetic nor environmental factor alone explains the cause of the disease. So that suggests that it's probably not just a single gene or a single environmental agent that causes Parkinson's but rather some combination of the two. And, unfortunately, there haven't been a lot of studies to examine that relationship. This study is a good example of the direction that the Parkinson's research field needs to go to really start understanding the associations between genetics and environment and how they may contribute to the disease.
MJFF: In fact, this study didn't find an association between the ABCB1 gene and PD until they added the environmental exposures, correct?
JR: Absolutely correct. Although there have been some mixed reports about the link between ABCB1 and PD, in this study the gene was only associated with PD in combination with pesticide exposure. So that is very interesting. And I think it's also important to remember that the association was only found in men who were highly exposed because they were directly applying these pesticides.
MJFF: So what does this type of study tell us about the association between genes, environment and PD?
JR: One of the major issues with studying environmental factors is that reconstructing exposure history is extremely complex. This type of study, a case-control study, looks retrospectively at information from people who have a disease, the cases, and compares that information to people who do not have the disease, the controls, to see if there are any other differences between the groups that might be contributing to the onset of disease. The authors of this study did a really good job -- one of the best I've seen -- of reconstructing as best they can the historical exposures based on retrospective data. But we can't infer causation with this type of study. So we can't say that if you have a certain variation in the ABCB1 gene and you've been exposed to high levels of pesticides that you're going to get PD. We can only say that the people in this study demonstrated a greater risk of getting the disease. More studies are needed to determine whether this association holds in other populations, particularly for the general public which presumably are not as highly exposed as the individuals in this study.
MJFF: And that's a big challenge for environmental researchers, correct? That it's difficult to prove causation?
JR: That's absolutely correct. Some rare instances have been able to demonstrate a one to one relationship. Take the MPTP story. Very young people started to mysteriously show up with Parkinsonism. Dr. Langston's team identified the chemical MPTP as a potential culprit, their group and others put it into a laboratory model and showed that it could kill dopamine neurons and cause many of the symptoms of PD.
But for the most part we haven't been able to do that with other environmental factors. However, epidemiological studies, like case-control studies, can help shed light on the associations between disease and environmental factors, like pesticides. And laboratory experiments can help us understand the underlying biological mechanisms of pesticides and their interactions with genetic factors that might lead to PD. We now know that a pesticide doesn't have to necessarily kill a dopamine neuron to lead to PD. It can cause other damage in the brain, like oxidative stress that can also lead to the disease. And that information is important to finding better treatments for PD.
MJFF: What are some of the other challenges in studying environmental factors?
JR: For one thing, environmental factors are very difficult to measure. Some of the newer pesticides are metabolized pretty quickly and they also don't persist in the environment for very long. So any time you measure one of those pesticides, you're really only looking at a snapshot in time. Organochlorine pesticides, the class that was assessed in this study, are unique because they are much more stable. Although organochlorines like DDT have been banned since the 1970s there are still substantial amounts in the environment. So we can actually measure organochlorines -- in the environment, in brain tissues and serum -- and emerging data says that, more often than not, they seem to be the pesticides that are associated with Parkinson's.
MJFF: You said earlier that these researchers did a really good job using retrospective data. How did they overcome some of the challenges of these types of studies?
JR: It's partly a function of the location. This study was conducted in France where PD is a list of 30 diseases for which you get free health coverage and I'm assuming that means there's some sort of registry and/or database. So the study authors were able to find information for a lot of subjects which makes the study stronger.
One of the big problems that we have in the United States is that there isn't a national registry for PD and there are only a few states, like California, Nebraska and Washington, where Parkinson's is a reportable disease like cancer. That's why cancer has always been ahead of Parkinson's disease in terms of epidemiological data -- because it's a reportable disease, there is a lot of data available. This kind of simplifies things. There are also more cancer cases than PD.
MJFF: What are the next steps for this area of research?
JR: The first step is to better understand the basic mechanisms of these interactions. We then may be able to use this knowledge to identify people who may be at a higher risk for PD. Once we can identify these people then the next step is to be able to track them by developing biomarkers that can give us insight as to whether or not neurological function is decreasing over time -- to be able to detect the onset of the disease early in the process. And the ultimate goal is to use all of this information to find interventions that can protect people from PD.