Inhaled Paraquat Found to Enter Brain, Affecting Sense of Smell in Male Mice

Prolonged, low-level inhalation of the common weed-killer paraquat, implicated in the risk of Parkinson’s disease, caused male mice to lose at least some of their sense of smell, a study reports.

This work also supported previous studies showing the inhaled chemical enters the brain via the olfactory nerve. As such, it may help in establishing more accurate risk assessments when setting herbicide limits to protect the public.

Sense of smell in exposed female mice, interestingly, was not significantly affected.

The study, “Paraquat Inhalation, a Translationally Relevant Route of Exposure: Disposition to the Brain and Male-Specific Olfactory Impairment in Mice,” was published in the journal Toxicological Sciences.

Paraquat has been linked to a higher Parkinson’s risk by its association with that disorder among agricultural workers exposed to this pesticide, and through studies showing that it can kill dopamine-producing neurons in mice. The loss of these neurons is a key event driving Parkinson’s progression.

Current U.S. pesticide regulations don’t always account for the effects of repeated low doses when setting limits. At the same time, animal studies assessing exposure risk rarely examine the effect of inhaled pesticides.

With this in mind, researchers at the University of Rochester, in New York, sought to compare the amount of paraquat that accumulated in various organs of mice when inhaling the substance at low levels, as opposed to the more common injection route.

“Inhalation can provide a direct route of entry to the brain,” Timothy Anderson, a graduate student and first author of the study, said in a university press release.

“If you inhale something and it goes into your nose,” he added, “it can actually enter the neurons responsible for sense of smell, and travel into the brain.”

These researchers also assessed changes related to sense of smell in exposed mice. In addition to being an early sign of Parkinson’s, olfactory impairment may serve as a sensitive indicator of pesticide exposure in humans.

Over 28 days, male and female mice were exposed to aerosolized paraquat for four hours a day, five days a week. At predefined time points, Anderson and colleagues measured paraquat levels in mice lungs and kidneys, and in four regions of the animals’ brain — the olfactory bulb, striatum, midbrain, and cerebellum.

Paraquat accumulated in all the examined tissues, with most found in the lungs and least in the kidneys. In the brain, the highest concentration of the herbicide was within the olfactory bulb, consistent with having entered by inhalation.

Brain levels of paraquat returned to near pre-exposure amounts at 28 days after final exposure, and were undetectable by the experiment’s end, approximately nine months after exposure terminated.

Investigators tested how inhaled paraquat might affect smell by training the mice to drink from water containing one particular scent, while avoiding water of another scent. They then mixed these scents in various ratios — from 100:0 to 70:30 — to test how well exposed mice could discriminate between the two.

Male mice that inhaled paraquat made significantly more “incorrect” choices — drinking water with the negatively associated scent, which also contained a bitter-tasting substance to encourage a proper choice — than did non-exposed males, even at time points corresponding to undetectable paraquat levels. Evidence of olfactory impairment persisted for months after paraquat exposure ended.

No significance was seen in the number of wrong water choices made by exposed female mice, indicating no major changes to their sense of smell.

Taken together, the team’s results imply that prolonged exposure to low levels of paraquat in the air allows it to enter the brain, where it changes males’ sense of smell in a way consistent with the trajectory of Parkinson’s onset.

Anderson next wants to study how paraquat affects specific brain region, and how this might impact motor skills, which decline over the course of Parkinson’s.

“These data,” the researchers concluded, “support the need for the establishing protective regulations for applying neurotoxic pesticides, such as [paraquat], in order to protect public health.”