Abstract
Periconceptional folic acid (FA) supplementation is recommended to prevent neural tube defects and other birth defects. After 20 years mandate food fortification with FA, serum concentration of folate and unmetabolized FA increased significantly in the North American population. But whether excess FA intake impairs neurodevelopment and behavior is still controversial. Here, we treated mice with approximately 2.5-fold (moderate dose of FA, MFA) or 10-fold (high dose of FA, HFA) the dietary requirement of FA 1 week before mating and throughout pregnancy and lactation, and examined behaviors in adult male offspring using open field test, three-chamber sociability and social novelty test, elevated plus maze, rotarod and Morris water maze. We found that early life MFA supplementation increased long-term body weight gain in adults, elevated anxiety-like behavior, and impaired social preference, motor learning and spatial learning ability without modifying motor ability and spatial memory. In contrast, HFA supplementation only induced mild behavioral abnormality. RNA sequencing revealed that FA supplementation altered the expression of brain genes at weaning, among which Fos and related genes were significantly up-regulated in MFA mice compared with control and HFA mice. Quantitative real time-PCR (qRT-PCR) and western blots confirmed the increase of these genes. Our results suggested that FA supplementation during early life stage affected gene expression in weaning mice, and exhibited long-term impairments in adult behaviors in a dose-sensitive manner.
Highlights
Folate is essential for nucleic acid synthesis and methylation reactions as a methyl donor in onecarbon metabolism (Anderson et al, 2012; Crider et al, 2012)
We found that mg/L FA (MFA) but not HFA activated Fos and related gene expression, and induced more behavioral abnormalities in adult male offspring, suggesting a dose-sensitive effect of folic acid (FA) supplementation on brain gene expression and long-term modification of behaviors
To investigate whether excess FA exposure before and during pregnancy and lactation affected physical growth of the offspring, the mice were supplied with 3.75 mg/L or 22.5 mg/L FA in their drinking water from 1 week prior to mating through postnatal day 21 (Figure 1A)
Summary
Folate is essential for nucleic acid synthesis and methylation reactions as a methyl donor in onecarbon metabolism (Anderson et al, 2012; Crider et al, 2012). Overwhelming evidence indicates that 0.4 mg per day of folic acid (FA), the synthetic. FA food fortification was mandated to decrease the incidence of NTDs in the United States, Canada, Chile and other countries since the late 1990s (Ray, 2004; Crider et al, 2011). Due to the FA supplementation and fortification, high concentrations of folate and unmetabolized FA (UMFA) are detected in most maternal and fetal circulation (Kelly et al, 1997; Obeid et al, 2010; Pfeiffer et al, 2012; Plumptre et al, 2015) as well as in breast milk (Page et al, 2017). Potential adverse effects of excess synthetic FA intake have begun to emerge
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