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Developmental exposure to methylmercury and resultant muscle mercury accumulation and adult motor deficits in mice.

ABSTRACT: Developmental methylmercury (MeHg) exposure can have lasting consequences on neural development and motor function across the lifespan. Recent evidence for MeHg targeting of myogenic pathways has drawn attention to the possibility that developing skeletal muscle plays a role in the motor deficits stemming from early life MeHg exposure. In this study we examined a potential role for muscle in influencing MeHg developmental toxicity in offspring of female mice exposed to MeHg via drinking water. Dams had access to 0, 0.5 or 5.0 ppm MeHg chloride in drinking water from two weeks prior to mating through weaning. Blood, brain and muscle tissue was harvested from dams at weaning and pups at postnatal days (PND) 6, 21 and 60 for analysis of total Hg. Muscle tissue sections were examined with histological stains. Behavioral testing of offspring was conducted at PND 60 and included locomotor activity, inverted screen, grip strength and rotarod tests to assess motor function. Total Hg (tHg) levels in dam muscles at weaning were 1.7-3-fold higher than Hg levels in blood or brain. In PND6 male and female pups, muscle and brain tHg levels were 2 to 4-fold higher than blood tHg. Brain tHg levels decreased more rapidly than muscle tHg levels between PND 6 and 21. Premised on modeling of growth dilution, brain tissue demonstrated an elimination of tHg while muscle tissue exhibited a net uptake of tHg between PND 6 and 21. Despite overall elevated Hg levels in developing muscle, no gross morphological or cytological phenotypes were observed in muscle at PND 60. At the higher MeHg dose, grip strength was reduced in both females and males at PND 60, whereas only male specific deficits were observed in locomotor activity and inverted screen tests with marginally significant deficits on rotarod. These findings highlight a potential role for developing skeletal muscle in mediating the neuromuscular insult of early life MeHg exposure.

SUBMITTER: Rand MD

PROVIDER: S-EPMC7708410 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Selenium (Se) leaches into water from agricultural soils and from storage sites for coal fly ash. Se toxicity causes population and community level effects in fishes and birds. We used the laboratory aquarium model fish, Japanese medaka (Oryzias latipes), an asynchronous breeder, to determine aspects of uptake in adults and resultant developmental toxicity in their offspring. The superior imaging properties of the model enabled detailed descriptions of phenotypic alterations not commonly reported in the existing Se literature. Adult males and females in treatment groups were exposed, separately and together, to a dry diet spiked with 0, 12.5, 25, or 50 μg/g (dry weight) seleno-L-methionine (SeMet) for 6 days, and their embryo progeny collected for 5 days, maintained under controlled conditions and observed daily for hatchability, mortality and/or developmental toxicity. Sites of alteration included: craniofacial, pericardium and abdomen (Pc/Ab), notochord, gall bladder, spleen, blood, and swim bladder. Next, adult tissue Se concentrations (liver, skeletal muscle, ovary and testis) were determined and compared in treatment groups of bred and unbred individuals. No significant difference was found across treatment groups at the various SeMet concentrations; and, subsequent analysis compared exposed vs. control in each of the treatment groups at 10 dpf. Increased embryo mortality was observed in all treatment groups, compared to controls, and embryos had a decreased hatching rate when both parents were exposed. Exposure resulted in significantly more total altered phenotypes than controls. When altered phenotypes following exposure of both parents were higher than maternal only exposure, a male role was suggested. The comparisons between treatment groups revealed that particular types of phenotypic change may be driven by the sex of the exposed parent. Additionally, breeding reduced Se concentrations in some adult tissues, specifically the liver of exposed females and skeletal muscle of exposed males. Detailed phenotypic analysis of progeny from SeMet exposed parents should inform investigations of later life stages in an effort to determine consequences of early life exposure.

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Developmental exposure to methylmercury and resultant muscle mercury accumulation and adult motor deficits in mice.

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