Paraquat Inhalation Produces Male-Biased Dopaminergic Neuron Loss and Motor Deficits in Mice: Relevance to Parkinsons Disease

Abstract

Long-term exposure to paraquat (PQ), a widely used herbicide, has been linked to increased risk of Parkinsons Disease (PD) in agricultural workers and rural communities in the United States (US), findings further supported by experimental animal studies. Although banned in many countries across the globe, PQ remains widely used in the US. Inhalation of PQ has been known to induce systemic organ failure at acute concentrations. However, prolonged low-dose inhalation from agricultural spraying and pesticide drift has not been readily evaluated for its potential to contribute to neurodegenerative diseases in vivo. Instead, many experimental studies have relied on systemic routes of exposure, which do not effectively replicate the most common route of exposure to PQ in the environment. In the current study, Parkinsonian features were examined in mice that had been exposed via whole-body inhalation to PQ aerosol for either 40 or 60 days. Levels of PQ in brain were highest in olfactory bulb, followed by frontal cortex and then brainstem in both sexes. After 60 days of exposure, male-specific impairments in locomotor activity were observed, in addition to reductions in striatal dopamine, in substantia nigra tyrosine hydroxylase (TH) expression and number of TH+ dopaminergic neurons, the latter being considered the primary basis of PD, along with increased olfactory bulb -synuclein levels. As such, these studies confirm the dopaminergic neurotoxicity of inhaled PQ. These findings raise significant concerns as to the contribution of PQ exposures to the continued increase in the incidence of PD in the US.