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Experimental maternal hyperpipecolatemia decreases DNA in the mouse brain
J S Kim1, M C Gutierrez, E Giacobini
1Department of Pharmacology, Southern Illinois University, School of Medicine, Springfield 62708.
Summary
Maternal exposure to high levels of pipecolic acid (PA) during pregnancy reduces fetal mouse brain DNA content. This suggests prenatal PA exposure causes neurotoxicity, impacting neuronal development.
Area of Science:
- Neuroscience
- Developmental Biology
- Toxicology
Background:
- Pipecolic acid (PA) is a major lysine metabolite in the central nervous system (CNS).
- Hyperpipecolatemia, a condition of elevated PA levels, is associated with neurological abnormalities in human neonates.
Purpose of the Study:
- To investigate the neurotoxic effects of pipecolic acid by mimicking hyperpipecolatemia in a mouse model.
- To determine the critical developmental window for PA-induced neurotoxicity.
Main Methods:
- Pregnant mice were administered pipecolic acid (250 mg/kg) during gestation to achieve high prenatal PA concentrations.
- Offspring were assessed for histological changes, and levels of DNA, RNA, and protein in the brain.
- Postnatal PA exposure was also evaluated in a separate cohort.
Main Results:
- Prenatal PA exposure led to a significant decrease in cortical and whole brain DNA content in offspring.
- No significant alterations were observed in brain, liver, or kidney histology, nor in protein, RNA, or CNPase activity.
- Postnatal PA exposure did not affect cortical DNA content, indicating a prenatal vulnerability.
Conclusions:
- High prenatal pipecolic acid levels induce a neurotoxic effect on fetal mouse brain development, specifically impacting cell proliferation.
- The prenatal period represents a critical window for pipecolic acid neurotoxicity due to the vulnerability of developing neurons.
- These findings may explain neuronal damage observed in hyperpipecolatemic neonates.