Manganese-induced Parkinsonism in mice is reduced using a novel contaminated water sediment exposure model

Abstract

The effects of heavy metals on human health have become an important area of study. For instance, acute manganese toxicity is known to induce Parkinsonism. Heavy metals including manganese enter the aquatic environment from both anthropogenic and natural processes. These metals accumulate within water sediments and their behavior is then dependent upon the sediment composition and phase. These metalsediment interactions remain to be explored within in-vivo animal studies. To study the effect of these interactions, herein we successfully developed an exposure model in mice that encapsulates the aquatic microenvironment of heavy metals before exposure. Male and female C57/BL6 mice were exposed to manganese contaminated sediment via their drinking water (Sed_Mn) or to manganese placed directly into their drinking water with no prior sediment interaction (Mn) for six weeks. Sediment interaction did not alter total manganese in drinking water (mg/L) or weekly manganese consumption (mg) in males (54.9±1.5 mg) or females (44.6±1.0 mg) over the six-week exposure period. We analyzed motor impairment, a common feature in Parkinson's disease, using the beam traversal, cylinder, and accelerating rotarod behavioral tests. We observed Parkinson's like deficits in motor control in both treatment groups as early as four weeks of exposure in males but not in females. Intriguingly, mice given water incubated with manganese spiked sediment (Sed_Mn) performed better overall compared to mice given manganese directly in water (Mn) despite having similar exposure in males and females. Male Sed_Mn mice compared to Mn mice had a 146% reduction in time to cross the beam traversal test (p<0.05), a 10% increase in rearing activity in the cylinder test (p<0.05), and a 14% increase in time remaining on the rotarod (not significant). Female Sed_Mn mice compared to Mn mice had no change in the time to cross the beam traversal test, a 36% increase in rearing activity in the cylinder test (p<0.05), and a 35% increase in time on the rotarod (p<0.05). Our study indicates that metal-sediment interactions may alter metal toxicity in mammals and introduces a new exposure model to test the toxicity of metal contaminants of drinking water.

Cognitive, Sensory, and Motor Impairments Associated with Aluminium, Manganese, Mercury and Lead Exposures in the Onset of Neurodegeneration

“…had a shorter retention duration on the revolving rod than the control group (Chopra et al, 2021). Male Mn mice spent less time on the rota rod than control mice, according to Freeman et al (2020) the time spent on the rota rod by females after manganese exposure was not considerably reduced like that of the male. Daily intraperitoneal (i.p.)…”

“…However, when compared to controls, animals given 20 mg Mn/kg demonstrated a substantial reduction in the overall latency for falling off the rota rod (Cordova et al, 2013b) When comparing the Mn-treated group to the control group, Chopra et al (2021) found a substantial rise in the catalepsy bar test that indicated muscle rigidity as of day 7 in the Mn-treated group. In both male and female Mn mice, Freeman et al (2020) noted a decline in rearing behaviour. Males were much more affected than females by the duration of exposure in terms of rearing behaviour.…”

“…The rearing response, which requires less motor work to execute, demonstrates a better animal ability for habituation (Peixoto et al, 2007). Rearing refers to the lifting of the forelimbs onto the glass cylinder walls and enables analysis of motor coordination through untrained, instinctive exploration (Freeman et al, 2020). All physical activity that is not considered to be formal exercise falls under the category of ambulatory activity.…”

“…Rodent models are frequently used in toxicology studies to acquire mechanistic understanding of heavy metal exposure and chronic diseases. These experiments simulate exposures using invasive procedures like oral gavage or by repeatedly injecting some doses of heavy metal salts into the water supply (Freeman et al, 2020). Since heavy metals are constantly transformed by human activity rather than being created or destroyed expose to heavy metals is inevitable, they can provoke a countless variety of effects.…”

Preparatory work for the update of the tolerable upper intake levels for manganese

“…et al, 2022). Three studies were conducted in mice (Freeman et al, 2020;Krishna et al, 2014;Wilcox et al, 2022) and five studies in rats (Avila et al, 2010;Muthaiah et al, 2016;Nkpaa, Awogbindin, et al, 2019;Takacs et al, 2012;Zhang et al, 2021).…”