Posted by Shelley mentioned a study last week that suggested more and more young people are getting Parkinson’s Disease, and she wondered whether there was any utility in blaming our industrialized society based on the fact that certain compounds we produce can induce Parkinsonian symptoms. Let’s start by giving a brief overview of the systems involved before we attempt to answer that question.
The substantia nigra contains a collection of dopaminergic neurons that project to the striatum. Integrity of this pathway is essential for normal motor function, although this nigrostriatal system is capable of compensating for cell loss until it loses around 80% or more of its neurons. Loss of these neurons is one of the central features of Parkinson’s Disease, which for the most part has no known cause (idiopathic PD). There are some notable famous exceptions such as the boxer Muhammed Ali who likely had his triggered from repeated blows to the head, and a set of cases that developed in individuals exposed to MPTP, a byproduct of a street chemist’s failed attempt to produce a Demerol-like compound. MPTP is metabolized into MPP+, which is toxic to dopaminergic neurons and can cause a human to basically develop a PD-like disease after a few days of exposure.
Interestingly, some herbicides are now under scrutiny for a potential causal role in PD. One such example is Paraquat, which has a structure similar to that of MPP+
Of course, since nothing is simple in biology, you can’t demonstrate that Paraquat produces PD by simply injecting a rat with it and waiting a couple days. Paraquat doesn’t readily cross the blood-brain barrier and as such, prior studies have produced variable results using this herbicide. Additionally, duration of exposure has usually been kept short (a few days to a few weeks), which is inappropriate if one is concerned that long-term exposure might be part of the problem.
With that in mind, I now turn to a paper that examined the consequences of 4, 8, 12, or 24 week exposure to Paraquat on the nigrostriatal system of rats. The goal of this study was not to reproduce PD, but to see if preclinical toxicity of the system could be induced and whether duration of exposure mattered.
Lo and behold, they find that the number of dopaminergic neurons in the substantia nigra, as measured by tyrosine hydroxylase (TH) immunoreactivity (meaning the tissue was stained to make the TH-positive cells visible), is decreased following 24 weeks of exposure to Paraquat. TH is the rate-limiting enzyme in production of dopamine.
Looking at this next figure, we can see the effect that Paraquat exposure had on nigral dopaminergic neurons. The first group of bars (-4.8 mm relative to a landmark on the skull) represents the front of the nigra, and each successive group of bars is moving progressively farther through the structure until the end is reached (-5.8 mm). Paraquat seems to reduce the numbers of TH-positive dopaminergic neurons in the front of the structure, and then progressively farther back as length of exposure is increased. The whole nigra is affected by 24 weeks. This effect is somewhat odd, but may simply reflect the fact that the structure shrinks as damage accrues over time.
Next up is TH staining in the nigra. We see a control rat in A and a rat treated for 8 weeks in B. The picture is small so you’ll have to take my word that there are fewer cells in B, but the really noticeable feature here is that TH staining intensity in B is actually increased. This is because TH doesn’t just label cell bodies but also cell processes such as axons. Staining intensity is higher because the neurons are trying to compensate for damage; they respond by boosting TH production. Remember that TH is the rate-limiting step in production of dopamine. In C, we see the nigra of a rat treated for 24 weeks. Here, both TH-positive neuron number and TH staining intensity are drastically reduced, suggesting that the system is losing its ability to compensate for the insult.
Examining the striatum which is the target for nigral dopamine release, we see that TH-positive axon terminals are decreased as well following 24 weeks (H) relative to controls (G). It looks as if Paraquat may have a deleterious impact on the nigrostriatal dopaminergic pathway (and other transmitter systems that the paper explored, but which I left out for brevity’s sake).
But are the manipulations used in this experiment directly relevant to the human condition? Likely humans would ingest the pesticide orally, which can reduce the toxic effect of the herbicide. We may take in lower amounts than what was used in this study. Plus our brains just might react differently. And no attempt was made to determine whether PD-like behavioral deficits were present, although given the fact that dopaminergic cell loss was only around 40% I find this unlikely.
So the broad take-home message is that yes, environmental compounds may act to compromise neural systems over time, in ways that suggest a role in certain diseases and conditions. Whether the particular line of research represented here can be extrapolated to humans is still up for grabs, but remember that elucidating the aetiology of idiopathic diseases such as PD is not a one-shot answer; demonstrating that Paraquat “causes” PD is not likely to happen. There is evidence that the effects of Paraquat are greatly increased, however, by concomitant exposure to the fungicidal agent Maneb. Other compounds may also play a role, as might time, duration of exposure, developmental stage at exposure, or a whole host of other factors. There is unlikely to be direct culpability on the part of a particular pesticide manufacturer, as a confluence of environmental and genetic factors may be required to trigger PD and other diseases. However, we should not rule out removal or limitation of one or two key factors in order to produce a significant public health benefit.
Ref:
Ossowska, K., Wardas, J., Śmiałowska, M., Kuter, K., Lenda, T., Wierońska, J. M., Zięba, B., Nowak, P., Dąbrowska, J., Bortel, A., Kwieciński, A. & Wolfarth, S. (2005) European Journal of Neuroscience 22 (6), 1294-1304.
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