Neurotopia

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.

i-c03af724b650b4c01301de35562cd9c9-th bar graph 1.jpg
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.

i-5c6f231daa367c860c6ee04b32c28a0b-th bar graph 2 copy.jpgLooking 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.

i-44ccf001c4906b5647cd04cd4d9c0808-SN micrograph.jpgNext 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.

i-7b1e2a4eb6cf020c80506a8f46a8381a-striatum micrograph.jpgExamining 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.

Comments

  1. #1 BilZ0r
    July 16, 2006

    What kind of dose of paraquat are we talking about here? Is it a relevant environment concentration? I know rotenone (AKA Deris dust) is another pesticide that can do the same (nigral cell degeneration), and I believe there are cases of people who suffered work-place poisoning, and latter developed Parkinson’s due to rotenone. Do you know whether cases like this have been reported for paraquat.

    Another reason for anyone who may have smoked Paraquat Pot in the 70s and 80s to be concerned.

  2. #2 Evil Monkey
    July 16, 2006

    The dose was 10 mg/kg i.p. every week. I don’t know what that means in terms of a brain concentration. I suspect it is a pharmacological dose. I didn’t see anything on a brief Pubmed search indicating that acute Paraquat exposure could induce a Parkinsonian state. The “multiple hit” hypothesis looks to be more fruitful, as does prolonged exposure.

  3. #3 BilZ0r
    July 16, 2006

    Mmmm, I geuss you’d have to either be spraying a lot of weed, or be very liberal with your application to get a 10mg/kg dose. But yeah, multiple hit really seems to be the only explanation, gene X environment interactions.

  4. #4 Shelley Batts
    July 17, 2006

    Thanks for expanding on this topic, evil monkey! Good intro and data. Two thoughts: One, I wouldn’t be surprised if the pesticide dopaminergic toxicity is most pronouced in those people who have a slight genetic predisposition to Parkinsons OR have had a head injury. The decline would likely be faster and more disasterous. Therefore someone might want to repeat this experiment in a young animal model for Parkinsons, and compare notes.

    Two, 24 weeks was an odd place to stop, when you assume that it is lifetime load (of at least 20-30 years) which might result in PD-type symptoms. Given, that is more difficult to replicate, but probably more relevent.

  5. #5 SkookumPlanet
    July 17, 2006

    I wrote a sentence in my previous post that’s the exact opposite of what I intended. Here’s the entire paragraph, corrected.

    It’s hard to imagine that even the manufacturers would publically accept this as wise. Yet, we can readily imagine it unfair to expect that untrained, unknowledgable managers across the nation with real-world problems to solve would, or could, come up with alternatives.

  6. #6 SkookumPlanet
    July 17, 2006

    Whoops….

    That’s two mistakes. I thought the correction would be held for review. A previous post hasn’t appeared. Sorry.

  7. #7 Evil Monkey
    July 17, 2006

    Not to be rude, but Parkinson’s is a real-world problem to solve. It costs us billions every year to care for these patients, plus time lost as relatives have to pick up the slack. So I’m less concerned with what the managers or even the manufacturers can do as I am with preventing a public health crisis of our own making.

  8. #8 SkookumPlanet
    July 17, 2006

    I just got back home. The “correction” was posted just before I had to go out. You’re not being rude and I agree with you 100%, as does the original post. The passage is pointing to a reality that’s ultimately politcal, but might also be a target for better scientific baseline research.

    In the last few weeks, several late night [west coast time] posts of mine were “held” by the system and never posted. I assumed too much off topic for the blogger. Perhaps they were system hiccups and guess I should repost in such circumstances.

    A summary, which isn’t really in the original: I’ve had a general interest from several angles over 20 years in pesticide issues, especially exposure. My inuition/analysis is that exposure data reflects detailed reality poorly. I’ve not read literature on this. I’ve included several stories illustrating this.

    Also, I’m just beginning an interest in dopaminergic everything, so I wanted to participate. Here’s the context for my correction which I posted late last night.
    .
    .
    Thanks for doing this.

    I’ll extend the idea some. While these dynamics are about obvious, overt illness and the difficulty making cause and effect connections, it’s possible such profound connections produce ambiguous, highly complex, synergistic effects that present as other, poorly defined illnesses in smaller doses.

    Gulf War Syndrome immediately comes to mind. One avenue being pursued in GWS [from memory] are one or more enzymes that are neuroprotective against organophosphate damage. GIs with GWS were exposed to a witch’s brew of substances who’s synergistic effects may never be understood, including insecticide impregnated clothing. My understanding is production of these enzymes are quite variable between individuals and likely genetically controlled.

    About 15 years ago, through multiple articles in a San Francisco newspaper, I followed a story about a group of disability claimants arguing in administrative court they’d been made ill, what was then called environmental illness, by pesticide spraying by their employer at their workplace. They were dealers in a Lake Tahoe casino. They identified a specific spraying incident. One can imagine, in their 24/7/365 single-floor, sealed casino-restaurant-kitchen, the employer’s concern with vermin. Through discovery the claimants obtained the casino’s previous year’s extermination records. “Professional” [it's a rural resort area] exterminators had come in and applied some sort of pesticide somewhere on that floor, on average, once every three days for a year. No notification was given to anyone in any way. This was not considered unusual practice.

    It’s hard to imagine that even the manufacturers would publicly accept this as wise. Yet, we can readily imagine [[it unfair to expect that]] untrained, unknowledgeable managers across the nation with real-world problems to solve would, or could, come up with alternatives.

    Over a year ago on German television [DW] I saw a half-hour, maybe an hour, program on several German women in their 30s or 40s highly damaged, needing assistance to walk, spastic arms and legs, etc. who’s pesticide exposure came from a decade or two unpacking shipments of cheap cotton clothing from south Asia for a German retail chain. Much of the show was shot in India and showed a highly unregulated, repackaged, unmarked pesticide distribution system to small plot, individual cotton farmers. Besides lots of obviously neurologically damaged people from farmers downstream, there were shots of farmers using backpack, pump sprayers spraying directly in front of themselves. They were walking their fields in a perpetual cloud of pesticide! I believe there was also more pesticide use in storage of fabric and clothing later on.

    No one interviewed from distributors on downstream had any knowledge of the dangers and appropriate use of pesticides. No one.

    Surprisingly, months after that show I received two internet-purchased, US-retailed, inexpensive white cotton bathrobes. On unsealing the first package, a heavy pesticide aroma erupted. It went immediately outside the house and I never opened the second package. Made in India.

    This is simply FYI and perhaps worthy of further coverage.

  9. #9 Evil Monkey
    July 17, 2006

    Incidentally, yes, we’ve been having a lot of commenting issues lately with our system.

  10. #10 Shelley Batts
    July 19, 2006

    Skookum- the reason why your post was held (and at my site too) was because you used the word in your post the spam filter didn’t like. If I use it, I will also be bloked, but its a place where people go to waste money in the desert. :)

  11. #11 SkookumPlanet
    July 24, 2006

    I had some time to track down the GWS “enzyme” I vaguely remembered, actually two of them. One is paraoxonase, product of gene Pon1, which I know nothing about other than in the late 90s researchers at UT Southwestern Medical Center at Dallas, led by Dr. Robert Haley, chief of epidemiology published three epidemiological reports in JAMA on GWS, and the work has attracted recent attention during congressional oversight of GWS research.

    The other is a product/gene, neuropathy target esterase[NTE]. From a GWS web page, “OPs in the bloodstream bind with the enzyme NTE, which is attached to neural membranes throughout the nervous system. The resulting organophosphorylated-NTE complex undergoes molecular reorganization over a one to six week aging period and forms a byproduct that is axonotoxic (Haley and Thomas, 1997). This time-dependent process which accounts for the delay between exposure and symptoms is called “aging” and OPs in which it occurs are called aging OPs.”

    Here’s a Salk Institute press release, Genetic Link May Tie Together Pesticides, ADHD, Gulf War syndrome and Other Disorders from 2003 about NTE. NTE has been identified recently in a microarray assay pilot study of Chronic Fatigue Syndrome patients that got hits on about two-dozen activated genes. NTE then ties together GWS, CFS, ADHD, and possibly PD. There’s a connection to the Lake Tahoe dealers also in that I’ve seen stats going as high as one third of CFS patients experience “environmental illness” symptoms. “EI” is now called Multiple Chemical Sensitivity, MCS, which I’ve seen defined as a stage one of Chemical Stress Syndrome. MCS gets periodic mention in the GWS research review discussions I’ve come across, and symptoms overlap GWS. Perhaps ADHD and PD aren’t the only dopamine-related problems.

    Later.
    Googling for Dr Haley’s name and the Pon1 reference I came across the following. It’s from the European Molecular Biology Organization’s EMBO reports. Title is Gulf War syndrome revisited, labeled “analysis”, at [http://www[dot]nature[dot]com/embor/journal/v4/n6/full/embor874[dot]html].

    Mutation of the PON1 gene is also associated with the development of Parkinson’s disease (I. Kondo & M. Yamamoto, Brain Research, 806, 271-273; 1998). Interestingly, sheep-dippers in the UK that had fatigue-cognitive-pain syndromes that are similar to GW syndrome and chronic fatigue syndrome, had the same gene variant (N. Cherry et al., Lancet, 359, 763-764; 2002).

    PD, ADHD, GWS, CFS, MCS. I also found a Science Daily item linking, via fMRI, Ritalin’s effects on the brains of ADHD kids and kids with “reading disorder.” The latter is undefined there and at some point I’ll chase that down. Perhaps it’s another set of initials to add to the list. And the name of the sheepherders’ disease? Maybe.

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    September 24, 2008

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    January 5, 2009

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  14. #14 Coastal Cowboy
    April 14, 2009

    I have parkinson, Essential Tremors, I’m 50 yrs old, during the 70′s daily usage of MJ, living bay area most of life. still us MJ on a daily basis. Long term exposure I am sure of since paraquat is still on MJ today out of mexico. So perhaps I have had long term exposure to the pesticides. And perhaps that is the real reason I am suffering now.
    I would like to pursue this, any course of action offered be appreciated.

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  18. #18 SkookumPlanet
    October 6, 2009

    Three years ago, I thought my use of “sheepherders” at the end of my last post was an error. But no, the British government turned more or less all sheepherders into sheepdippers from 1976 to 1992 and gave them scant guidance or oversight. Same government set up mad cow disease despite advance warning by scientist. Lots of sheepdippers dipped their sheep in organophosphate

    And so the colloquial is Dipper’s Flu. The initials are COPIND [chronic organophosphate-induced neuropsychiatric disorder]. If you want colloquial, it’s Dippers’ Flu.

    Psychiatric aspects of chronic exposure to organophosphates: diagnosis and management
    [http://apt[dot]rcpsych[dot]org/cgi/content/full/6/5/356]

    Chronic exposure to organophosphates: background and clinical picture
    [http://apt[dot]rcpsych[dot]org/cgi/content/full/6/3/187]

    and apparently the most detailed description of symptoms

    Chronic Organophosphate Exposure: Towards the Definition of a Neuropsychiatric Syndrome [abstract]
    [http://www[dot]ingentaconnect[dot]com/routledg/cjne/1997/00000007/00000003/art00005]

    And reading disorder is now the accepted terminology for all neuro-based reading problems such as dyslexia.

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