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Published on: November 8, 2017
Monochloroacetic acid toxicity in the mouse associated with blood-brain barrier damage
M R Berardi1, R Snyder, R S Waritz
1Joint Graduate Program in Toxicology, Rutgers University, Piscataway, New Jersey.
Abstract:
Monochloroacetic acid (MCA) causes front paw rigidity in 10% of mice surviving a single oral toxic dose (320-380 mg/kg). Mice exhibiting front paw rigidity were killed at various times after MCA treatment and their brains were prepared for histological examination. As early as 48 hr post-treatment, RBCs were found outside capillaries in several brain regions, especially the cerebellum. At time points up to 8 weeks after MCA, extracapillary RBCs were seen to be undergoing lysis, and there was loss of cerebellar Purkinje cells. Three hours after oral administration of an LD80 of MCA (380 mg/kg), entry of iv-injected [14C]inulin or [3H]dopamine (1.0 microCi) into all brain regions was significantly increased compared to controls. Increased entry of [14C]inulin into the brains of mice occurred as early as 2 hr after MCA, coinciding with the onset of signs of toxicity, and remained elevated for up to 8 hr following treatment. Further studies revealed that only those mice which were moribund but not those which were unaffected by MCA (380 mg/kg) 4-6 hr after treatment had significantly increased brain levels of [14C]inulin or [3H]dopamine. However, mice which survived an LD80 of MCA and exhibited front paw rigidity 24 hr later also had brain radiotracer concentrations significantly greater than controls. Both the lethal effects of MCA and the physical deficits observed in survivors may be associated with impairment of blood-brain barrier function.
Insights
Monochloroacetic acid (MCA) causes brain capillary damage and cell loss in mice. This impairment of blood-brain barrier function may explain both lethal effects and physical deficits in survivors.
Area of Science:
- Neuroscience
- Toxicology
- Pathology
Background:
- Monochloroacetic acid (MCA) is a toxic chemical.
- MCA exposure can lead to neurological deficits in surviving mice, specifically front paw rigidity.
- The underlying mechanisms of MCA-induced neurotoxicity are not fully understood.
Purpose of the Study:
- To investigate the effects of Monochloroacetic acid (MCA) on the blood-brain barrier (BBB) in mice.
- To correlate BBB disruption with observed neurological deficits and cellular changes in the brain.
- To determine if BBB impairment is a key factor in MCA's toxicity.
Main Methods:
- Mice were administered a single oral toxic dose of MCA (320-380 mg/kg).
- Histological examination of brain tissue was performed at various time points post-treatment.
- Intravenous injection of radiolabeled tracers ([14C]inulin and [3H]dopamine) was used to assess BBB permeability.
- Brain tissue and tracer concentrations were quantified.
Main Results:
- Extravasation of red blood cells (RBCs) and subsequent lysis were observed in brain regions, particularly the cerebellum, starting 48 hours after MCA exposure.
- Significant loss of cerebellar Purkinje cells was noted up to 8 weeks post-MCA.
- Increased brain uptake of [14C]inulin and [3H]dopamine occurred as early as 2 hours after MCA administration, indicating BBB disruption.
- Elevated BBB permeability correlated with the onset of toxicity and persisted for up to 8 hours.
- Mice exhibiting signs of toxicity or neurological deficits (front paw rigidity) showed significantly increased brain radiotracer concentrations.
Conclusions:
- Monochloroacetic acid (MCA) significantly impairs blood-brain barrier (BBB) function in mice.
- MCA-induced BBB disruption is associated with extravasation of red blood cells, neuronal cell loss (Purkinje cells), and neurological deficits.
- Impairment of BBB function is a likely mechanism contributing to both the acute lethal effects and the long-term physical deficits observed after MCA exposure.
