The Environment and Parkinson's

Bette Hileman / Chemical and Engineering News v.79, n.38 17sep01

If exposure to chemicals causes this dread disease, regulators may have to alter approaches to neurotoxicity testing and risk assessment

The number of people with Parkinson's disease in the U.S. will surely rise as the population ages. Already, more than a million people, about 1% of the population over age 60, live with the disease. Despite years of effort, neither definitive causes of the disease nor effective long-term treatments have been found. Research efforts are increasing, however, and work on the combination of inheritance, age, and environmental exposures implicated in Parkinson's is starting to come together for a clearer picture--one that might ultimately alter regulations of some chemicals.

A conference held late last month in Colorado Springs made it clear that such research into causes and treatments for Parkinson's disease has reached an exciting stage of development. "A new optimism that Parkinson's can be defeated is energizing the research community," said meeting organizer Joan M. Cranmer of the department of pediatrics at the University of Arkansas for Medical Sciences (UAMS).

The meeting was sponsored by UAMS with support from the National Institute of Environmental Health Sciences (NIEHS), the Environmental Protection Agency (EPA), the Centers for Disease Control & Prevention (CDC), the Parkinson's Institute, and several other foundations and corporations. It brought together scientists from a wide variety of disciplines--toxicologists, chemists, neurologists, geneticists, epidemiologists, and clinicians.

CAUSE/EFFECT Loss of dopamine-producing neurons in the substantia nigra causes Parkinson's disease.

PARKINSON'S DISEASE is a progressive, incurable ailment, and the second most common neurodegenerative disorder in the U.S. It begins when a class of brain cells that produce dopamine start to die. Symptoms become apparent only after 60 to 80% of the cells are dead. The disease is characterized by resting tremor, rigidity, slow movement, postural instability, and progressively involuntary writhing movements, paralysis, and an inability to talk or even swallow. Dopamine is a chemical messenger that helps control muscles. Although the medication levodopa--a dopamine precursor--relieves many Parkinson's symptoms, its effectiveness declines as the disease progresses.

Speakers explained that many scientific pieces of the Parkinson's puzzle have been identified. "But assembling the elements into a coherent theory of the cause of Parkinson's disease still remains a major challenge," said J. William Langston, scientific director and founder of the Parkinson's Institute.

NIEHS Director Kenneth Olden announced at the meeting an NIEHS initiative that may accelerate progress in the field--a Consortium Centers Program. It will provide a formal mechanism for interactions between clinicians, basic research scientists, and patient advocates. It will seek to identify and support novel approaches and research ventures that might not otherwise be pursued by scientists working in isolation, he said.

Only about 10% of Parkinson's cases are familial--that is, clearly caused by genes. The remainder result from unknown factors such as insults from the environment or some interaction between genetic susceptibility and the environment. "Parkinson's disease appears to arise from the interaction of three events--the patients' inherited genetic susceptibility, their subsequent environmental exposures, and their age," Olden said at the meeting.

WHATEVER THE CAUSE, Parkinson's is found in every country and very little is known about incidence patterns over time, said Caroline M. Tanner, director of clinical research at the Parkinson's Institute.

In addition to Parkinson's disease, there is a condition called Parkinsonism that resembles Parkinson's. Parkinsonism is sometimes caused by exposure to manganese, carbon monoxide, or other toxicants and, unlike Parkinson's, is often reversible, Tanner said.

Several speakers at the meeting pointed out that regulators may need to alter their approaches to neurotoxicity testing and risk assessment because of evidence that some kinds of chemical exposures in the womb, during early childhood, or later may increase susceptibility to Parkinson's in old age. Under current government guidelines for two-generation assays, lab rodents are sacrificed at 60 days, long before susceptibilities induced in early life could result in the types of illnesses that might show up during the equivalent of a rodent's old age--1.5 to 2 years.

"Relatively little research has focused on adult or aging animals which may be differentially sensitive to toxicants due to a history of prior exposure," said Virginia C. Moser, toxicologist at the EPA National Health & Environmental Effects Research Laboratory in Research Triangle Park, N.C. Research on rodents during old age is critical to understanding the potential influences of exposures in early life, she said.

ESSENTIALLY three lines of evidence have led researchers to believe that chemical exposures, particularly to pesticides, play a role in some cases of Parkinson's. One is that people who live in farming areas, especially those who drink well water, and have a history of exposure to pesticides are more likely to contract Parkinson's. Another is that several studies have shown that those who die of Parkinson's disease have higher levels of organochlorine pesticides in their brains than the general population. A third is that in the early 1980s, a group of young people developed Parkinson's symptoms after taking an illegal drug called MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), whose structure is similar to meperidine, trade named Demerol. The structure of its metabolite MPP+ is also similar to the pesticide paraquat.

SUBSEQUENTLY, monkeys were fed MPTP, and they too developed Parkinson's symptoms. Researchers also found that paraquat, maneb, and rotenone, as well as a number of other pesticides, cause Parkinson's-like symptoms in rodents and nonhuman primates.

However, the mechanism by which Parkinson's is induced by pesticides--if indeed they cause some fraction of the disease in humans--is not yet well understood, and cause-effect relationships between pesticides and Parkinson's are still unclear.

Spokesmen from the pesticide industry, such as Michael J. L. Clapp of Syngenta, insist that real-world exposures to pesticides are too low to cause Parkinson's. For example, people have very little exposure to paraquat, he said.

One factor that complicates all epidemiological work on Parkinson's is that there is no lab test--no biomarker--to establish definitively that a patient has the disease. In fact, it is not yet known whether Parkinson's is a single disease, or multiple diseases with many different causes. "Parkinson's may be a constellation of disorders," said Donato DiMonte, director of basic research at the Parkinson's Institute.

One of the hallmarks of Parkinson's is the aggregation of the protein a-synuclein into insoluble fibrils that form microscopic inclusions called Lewy bodies. After death, Lewy bodies can be detected in the substantia nigra, a small structure in the midbrain, of nearly all Parkinson's victims as well as in the brains of victims of some other neurologic disorders. Lewy bodies are concentric, intracellular inclusions with peripheral halos and dense cores. Most researchers believe a-synuclein aggregates into fibrils when it suffers some sort of oxidative damage.

Anthony L. Fink, chemistry professor at the University of California, Santa Cruz, has a different theory. He presented evidence that micromolar concentrations of several pesticides and some metal chlorides accelerate the rate of formation of a-synuclein fibrils in vitro. "The most effective pesticides were rotenone, dieldrin, DDT, 2,4-D, and paraquat," he said. For example, DDT caused a sixfold acceleration in the fibrillation rate, but glyphosate (Roundup) had no effect. Relatively insoluble hydrophobic pesticides bind to the negative parts of a-synuclein and shift the equilibrium from a natively unfolded to a partially folded intermediate conformation, he suggested.

Among metals, aluminum(III), copper(II), iron(III), cobalt(III), and manganese(II) were the most effective at accelerating the formation of a-synuclein fibrils. "The effectiveness of the metals"--which likely bind to the negative parts of a-synuclein and stabilize the partially folded intermediate--"correlates with increasing ion charge density," he said.

FINK ALSO FOUND that mixtures of metals and pesticides can have a synergistic effect on a-synuclein fibrillation. "Although the concentrations we use in our experiments are relatively high compared with what we see in brains, mixtures of pesticides or metals at much lower levels may have major effects in humans," he explained. "If a-synuclein fibrillation is the crucial causative factor in Parkinson's disease, then compounds that prevent the aggregation may have potential as therapeutic agents in disease treatment, he suggested.

Fink and his coworkers also gave mixtures of aluminum and diethyldithiocarbamate (DDC) to mice and obtained evidence that the mixtures cause a-synuclein inclusions in the substantia nigra of the treated mice.

J. Timothy Greenamyre, a professor in the department of neurology and pharmacology at Emory University, believes rotenone causes Parkinson's symptoms through oxidative stress. He treated rats with very low levels of rotenone--between 0.5 and 0.00005 times the usual doses employed in Parkinson's research. He found that rotenone caused degeneration of the nerve cells that produce dopamine in the substantia nigra. The rats developed inclusions in the substantia nigra that are fibrillar, but not identical to Lewy bodies, he said, and the rats' movements--slow and rigid--resembled those of Parkinson's patients.

"We think the rotenone was causing oxidative stress and increasing the production of a-synuclein," Greenamyre said. Subsequently, the a-synuclein became insoluble and formed protofibrils, he explained.

Rotenone is a natural compound derived from the roots of tropical plants. Generally considered relatively harmless to mammals, it is used to kill nuisance fish in lakes, insects in gardens, and fleas and ticks in pets. Some foresters bathe in it after working in the woods.

Richard F. Seegal of the New York State Department of Health, reported on studies to determine whether polychlorinated biphenyls (PCBs) are a risk factor for Parkinson's disease. In one study, he exposed nonhuman primates to 3.2 mg per kg body weight per day of PCBs for 20 weeks. As a result, dopamine concentrations in the primates' basal ganglia were reduced by 20% and remained depressed after PCB treatment ceased.

Seegal also conducted a pilot study to examine the potential central nervous system effects of PCBs in 10 aging capacitor workers who had been heavily exposed to PCBs. Compared with matched controls, tremor, rigidity, and slowness of movement had increased in the workers; verbal memory and reaction times were also reduced. Archived serum from the workers shows that when exposure ceased, PCB levels were the same as the PCB levels in the primates, he said.

Elena Herrero Hernandez, a specialist in occupational medicine at the University of Turin, in Italy, discussed the cases of two welders whose heavy exposure to manganese had caused Parkinsonism. Both had worked without protective equipment, one for 25 years and the other for 31 years. They had similar neurologic symptoms--postural tremor mainly in the upper limbs, weak muscles, slow movements, and elevated blood levels of manganese.

AFTER THE TWO MEN were given chelation therapy, their blood levels of Mn dropped into the normal range and their neurologic symptoms improved. When patients have symptoms of Parkinson's, a careful occupational history should be taken to determine if the patient has been overexposed to manganese, Hernandez said. Parkinsonism induced by manganese is often misdiagnosed as ordinary sporadic Parkinson's disease, she explained.

Parkinson's disease is unusual because its incidence seems to be decreased by a person's use of tobacco, caffeine, and alcohol. The strongest preventive agent seems to be tobacco. According to G. Webster Ross, a researcher at the Parkinson's Institute, more than 35 epidemiological studies have consistently demonstrated an inverse association between years of smoking and risk of Parkinson's. This inverse association "is reported for every continent and every race," he said. "The odds ratios, in these studies, cluster around 0.5," he said, which means that smokers have about half the risk of contracting Parkinson's as nonsmokers. One possible explanation for this phenomenon is that nicotine stimulates the release of dopamine in the striatum. In laboratory animals with lesioned pathways in the substantia nigra, nicotine preserves striatal dopamine levels.

Drinking caffeinated coffee years before the onset of Parkinson's disease has also been shown to be inversely related to Parkinson's disease risk, Ross said. In a 1975 study, for example, people who did not drink coffee had five times the risk of Parkinson's as those who drank coffee. The explanation may be that caffeine reduces the toxicity of neurotoxins, he explained.

THE EVIDENCE that alcohol reduces the risk of contracting Parkinson's disease is not as strong. In one study, the consumption of beer and spirits, but not wine, was inversely associated with the incidence of Parkinson's, Ross said.

At the meeting, several experts speculated that it is not nicotine or caffeine or alcohol that prevents Parkinson's but something related to the personalities of the people who use these substances. People who engage in these activities have pleasure-seeking personalities, the researchers said, and there might be some physiological factor in the brains of such individuals--a high level of dopamine, for example--that helps to resist Parkinson's.

Not all scientists who study Parkinson's agree that the environment plays a role in Parkinson's disease. Matthew Farrer of the department of neuroscience and neurology at the Mayo Clinic in Jacksonville, Fla., believes that genes are primarily responsible for the disease. The most productive research will be studies of genetic variants in the population to see whether they contribute to risk, he said.

At the close of the meeting, speakers expressed optimism that rapid progress in understanding Parkinson's is likely in the near future. "Hopefully, in a few years, we will be talking about concrete action to prevent the disease," said DiMonte. "We do have clues. We do have incredible models. We do have compounds that can reproduce the disease. We have accomplished a great deal," he said.

DYSFUNCTION

Checking Out The Manganese Connection

One factor researchers have associated with Parkinson's disease is exposure to manganese. Workers who are heavily exposed to manganese develop Parkinson's-like symptoms, and manganese has also been implicated as a causal agent in attention deficit hyperactivity disorder. Both of these conditions involve dysfunction in brain dopamine systems.

And there is some concern that very early exposure to manganese could create problems later on. For example, infant formulas contain considerably higher levels of manganese than does human breast milk. The manganese concentration in breast milk is 3 to 10 µg per L; in formula based on cow's milk, it is about 30 µg per L; and in soy formula, which is often given to babies who are allergic to cow's milk, the manganese level is 150 to 1,000 µg per L.

To explore the potential effects that a high intake of manganese might have on human infants, Trinh T. Tran of the department of nutrition at the University of California, Davis, studied the effects of manganese on newborn rats. She divided the rats into four groups and supplemented their diets with 0, 50, 250, and 500 µg of manganese per day until they were 20 days old.

In a test of homing skills, the group most heavily exposed did not do nearly so well as the control group, Tran says. Also, there was an inverse relationship between manganese exposure and striatal dopamine levels in the rats' brains. (Dopamine levels also decline in Parkinson's disease patients.) "These observations suggest that dietary exposure to high levels of manganese during infancy can be neurotoxic to rat pups and result in developmental and neurocognitive deficits," Tran says.

source: http://pubs.acs.org/email/cen/html/091801045059.html 18sep01