Prenatal Monosodium Glutamate Causes Long‐Lasting Cholinergic and Adrenergic Changes in Various Brain Regions

Abstract

Prenatal monosodium glutamate (MSG) given through the mother's diet was found previously to cause behavioral changes in the offspring, including learning disabilities. In the present study, neurochemical parameters were measured in the brains of prenatally exposed rats at various ages throughout development up to adulthood. At 15 days of age, choline uptake and choline acetyltransferase (ChAT) activity in the frontal cortex were significantly reduced (by 80 and 25%, respectively) in MSG-exposed animals, whereas the same cholinergic parameters in hippocampus were not changed. During later development, choline uptake gradually increased, until in adulthood it became significantly higher in MSG-exposed animals than in the controls. This enhancement was found in both males and females. Our previous study showed that only the male offspring were learning disabled. Choline uptake and ChAT activity were enhanced in the hippocampus of adult male animals. Norepinephrine (NE) uptake was reduced (by 25%) in the frontal cortex of males only. There was no change in NE uptake in the hypothalamus.

A Test of Dietary Monosodium Glutamate Developmental Neurotoxicity in Rats: A Reappraisal

“…In a second study from this group [19], they gave MSG in drinking water at the same concentration as in their previous study to gravid Wistar rats on the same gestational days (the last 14 days of pregnancy up to E20) as before. The outcomes assessed in this experiment were 3 H-choline, norepinephrine (NE), and GABA (gammaamino butyric acid) uptake into selected brain regions in synaptosomal fractions, and 14 C-acetyl-CoA uptake, as a marker of choline acetyltransferase activity, in crude fractions.…”

“…Two studies were done in Wistar rats, exposing them to MSG in their drinking water during the last 2 weeks of gestation [18,19]. In the first study [18], MSG was provided as 5 g/100 mL of water resulting in an estimated dose of 10 g/kg.…”

Risk Assessment Paradigm for Glutamate

“…Furthermore, the endpoints tested were in an experimental stage and were never included in later OECD protocols for neurodevelopmental toxicity testing [59], because of a high degree of variability, leading eventually to the conclusions that these findings do not exhibit a pattern of developmental neurotoxicity (Vorhees et al [3], this issue). In addition, other reproductive and (neuro)developmental toxicity studies reveal higher NOAEL values, including the highest dose level tested of 6,000 mg/kg bw/day in the 3-generation reproductive toxicity study in mice as the most sensitive species reported by Anantharaman [47] that also performed extensive histopathology of brain tissue, and the only dose tested of 10,000 mg/kg bw/day in the developmental neurobehavior study reported by Frieder and Grimm [55,56] on which the EFSA concluded that there were no adverse effects when corrected for multiple testing. Considering the study of Vorhees et al [3] to be inappropriate for human risk assessment, these other studies provide a point of departure that is higher than 6,000 mg/kg bw/day and perhaps even higher than 10,000 mg/kg bw/day.…”

Immune-Glutamatergic Dysfunction as a Central Mechanism of the Autism Spectrum Disorders

“…Frieder and Grimm [113,114] have demonstrated that feeding MSG to pregnant rats can lead to severe alterations in learning that only affected the male rats, again demonstrating a male preponderance of toxic effects. It has also been shown that sensitivity to glutamate increases after birth [115,116].…”

“…Of great concern is the finding of MartinezContreras et al [119] that glutamate can prime microglia, leading to brain inflammation and high levels of inflammatory cytokines in the brain. In addition, some studies [114,120] have demonstrated alteration in hippocampal architecture and synaptic development following neonatal exposure to MSG in animal models.…”