Age and Chronicity of Administration Dramatically Influenced the Impact of Low Dose Paraquat Exposure on Behavior and Hypothalamic-Pituitary-Adrenal Activity

Abstract

Little is known of the age-dependent and long-term consequences of low exposure levels of the herbicide and dopaminergic toxicant, paraquat. Thus, we assessed the dose-dependent effects of paraquat using a typical short-term (3 week) exposure procedure, followed by an assessment of the effects of chronic (16 weeks) exposure to a very low dose (1/10th of what previously induced dopaminergic neuronal damage). Short term paraquat treatment dose-dependently induced deficits in locomotion, sucrose preference and Y-maze performance. Chronic low dose paraquat treatment had a very different pattern of effects that were also dependent upon the age of the animal: in direct contrast to the short-term effects, chronic low dose paraquat increased sucrose consumption and reduced forced swim test (FST) immobility. Yet these effects were age-dependent, only emerging in mice older than 13 months. Likewise, Y-maze spontaneous alternations and home cage activity were dramatically altered as a function of age and paraquat chronicity. In both the short and long-term exposure studies, increased corticosterone and altered hippocampal glucocorticoid receptor (GR) levels were induced by paraquat, but surprisingly these effects were blunted in the older mice. Thus, paraquat clearly acts as a systemic stressor in terms of corticoid signaling and behavioral outcomes, but that paradoxical effects may occur with: (a) repeated exposure at; (b) very low doses; and (c) older age. Collectively, these data raise the possibility that repeated “hits” with low doses of paraquat in combination with aging processes might have promoted compensatory outcomes.

The Impact of Methylenetetrahydrofolate Reductase (MTHFR) Deficiency in a Paraquat Mouse Model of Parkinson’s Disease

“…It is therefore possible that this injection protocol did not have the potency required to induce a significant amount of degeneration. However, a similar 6 injection procedure has been employed by other studies, and has been able to elicit significant neurodegenerative effects (Jiao et al, 2012;Rudyk et al, 2017;Thiruchelvam et al, 2003), allowing for the possibility that it is other factors that are responsible for this difference.…”

“…It has been shown to alter NE signalling in the locus coeruleus (LC), paraventricular nucleus (PVN) of the hypothalamus, and hippocampus (Litteljohn, Mangano, Shukla, & Hayley, 2009;Litteljohn, Nelson, Bethune, & Hayley, 2011;Rudyk, Litteljohn, Syed, Dwyer, & Hayley, 2015). Decreased 5-HT in the medial prefrontal cortex (mPFC) and dorsal hippocampus has been demonstrated following paraquat treatment (Litteljohn et al, 2009), as well as reductions in glucocorticoid receptors in the hippocampus (Rudyk et al, 2017).…”

“…Thus, aging may provide an additional "hit" to mice in this model and affect the progression of damage. A study conducted on aged mice has also observed unexpected effects of chronic low dose paraquat treatment, suggesting such a treatment regimen may trigger different, perhaps even adaptive, processes in these mice (Rudyk et al, 2017).…”

Environmental toxicant exposure and Parkinson’s disease: LRRK2 and inflammatory processes

“…The present thesis experiments seek to investigate the pesticide, paraquat, either alone or in combination with the inflammatory endotoxin, LPS. Previous work in our laboratory has substantially explored these models, and found them to elicit highly reproducible PD-like behavioral and biological pathology [42,48,50,[139][140][141]. Meta-analyses and epidemiological studies primarily conducted on agricultural communities have demonstrated a strong link between pesticides and PD in humans [142][143][144].…”

“…In fact, the highest levels of LRRK2 were found in peripheral lymphocytes and monocytes of PD patients [323] and LRRK2 mutations have been associated with microglial reactivity and pro-inflammatory cytokine production in the brain and periphery [278,[324][325][326]. Moreover, typical inflammatory agents, such as lipopolysaccharide (LPS), as well as chemical toxicants like MPTP, that are used to model PD pathology, have been shown to influence processes linked to LRRK2 [104,140,327].…”