After three weeks of exposure to a pesticide, the laboratory mice moved slowly and had difficulty finding their balance.
Scientists were using this chemical to study some of the movement problems seen in Parkinson’s disease. But as they continued to monitor the animals after the exhibit ended, these problems began to lessen.
Without receiving treatment to reverse their symptoms, the mice gradually improved. After a year, they performed movement tests as well as age-matched controls.
Neuroscientist Xuelin Lou of the Medical College of Wisconsin told ScienceAlert that the resolution of these Parkinson’s-like deficits was “totally unexpected.”
In a study published in iScienceLou and his colleagues, cell biologist Prince Joshi and physiologist Fan Fan, studied what happened long after exposure to the pesticide rotenone ended.
Parkinson’s disease damages the cells that produce dopamine, a chemical that helps control movement. Rotenone mimics some features of the disease in animals by interfering with tiny energy-producing structures inside cells called mitochondria.
Exposure to rotenone and some other pesticides has also been linked to a higher risk of Parkinson’s disease in humans. However, these associations are not sufficient to establish a causal link.
Most experiments using rotenone models focus on early effects.
Researchers gave young adult male mice daily injections of rotenone for 21 days. Control mice received the same injectable mixture without the toxin.
Graphical summary of the experiment showing early movement difficulties and long-term recovery in mice exposed to rotenone. (Joshi et al., iScience2026, CC BY 4.0)
Four weeks after the experiment began, the exposed mice ran shorter distances, moved more slowly, and had difficulty staying on a rotating rod used to assess balance and coordination. They also spent less time exploring the open, wallless arms of an elevated maze, a measure of anxious behavior.
Longer follow-up revealed a progressive change.
In the open-field movement test, exposed mice reached control group levels in about four months. After seven months, their rotating rod performance was no longer significantly different from controls. At 12 months, the groups also performed similarly on anxiety-related tests.
Brain tissue offered a possible clue. The researchers looked at a region of the midbrain linked to movement, called the substantia nigra pars compacta.
They identified dopamine-producing cells using an enzyme needed to make dopamine, called tyrosine hydroxylase (TH). Shortly after exposure, the number and density of cells detectable with this marker were approximately 40% lower in exposed mice.
However, a second marker that marks neurons more broadly showed that total neuronal density was preserved.
“Our results suggest that they are simply losing their identity,” Lou said.
Some surviving cells may have produced too little TH to be identified as dopamine-producing neurons. Their disappearance from the count of positive TH does not establish that they are deceased.
At 12 months, the number and density of TH-positive cells were comparable between groups, although the enzyme signal remained lower in exposed mice.
Aging has complicated this comparison. Control mice examined at 12 months had approximately 45 percent lower TH-positive cell density than controls examined at baseline. In exposed mice, this density changed little between the two measurements. Lou said the reason for the difference is not known.
These tissue measurements came from different animals at each time point. Both groups’ rotating rod performance also declined as they aged, so matching the older controls did not mean reverting to their younger condition.
Lou explained that the recovery likely reflects both better functioning of the remaining dopamine-producing neurons and their resistance to age-related loss. Separating these contributions is difficult because the methods cannot track individual neurons over time.
The recovery mechanism is unclear. Lou said possibilities worth exploring include surviving neurons growing new branches, adjustments in their connections, and changes linking cellular metabolism to gene activity. The team is currently investigating the factors that drive this resilience.
Other scientists tested an experimental combination of drugs to treat Parkinson’s-like symptoms in mice. Here, the behavioral differences resolved without such intervention.
Only male mice were studied, with three to eight animals per group in the 12-month analyses, depending on the measurement.
The mouse models lacked several features of human Parkinson’s disease, including significant accumulation of an abnormally altered form of the protein alpha-synuclein. Rotenone can also cause muscle weakness and general illnesses that influence movement tests.
Lou cautioned that “the results do not imply that pesticide exposure is harmless nor refute the association between pesticide exposure and Parkinson’s disease risk.”
“The findings of this work should not be directly extrapolated to at-risk patients or workers,” Lou said.
Establishing the relevance of the findings to humans will require evidence from people or studies of dopamine-producing human cells and tissues.
The research was published in iScience.
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