Excess perigestational folic acid exposure induces metabolic dysfunction in post-natal life

Abstract

The aim of this study was to understand whether high folic acid (HFA) exposure during the perigestational period induces metabolic dysfunction in the offspring, later in life. To do this, female Sprague-Dawley rats (G0) were administered a dose of folic acid (FA) recommended for pregnancy (control, C, 2 mg FA/kg of diet, nZ5) or a high dose of FA (HFA, 40 mg FA/kg of diet, nZ5). Supplementation began at mating and lasted throughout pregnancy and lactation. Body weight and food and fluid intake were monitored in G0 and their offspring (G1) till G1 were 13 months of age. Metabolic blood profiles were assessed in G1 at 3 and 13 months of age (3M and 13M respectively). Both G0 and G1 HFA females had increased body weight gain when compared with controls, particularly 22 (G0) and 10 (G1) weeks after FA supplementation had been stopped. G1 female offspring of HFA mothers had increased glycemia at 3M, and both female and male G1 offspring of HFA mothers had decreased glucose tolerance at 13M, when compared with matched controls. At 13M, G1 female offspring of HFA mothers had increased insulin and decreased adiponectin levels, and G1 male offspring of HFA mothers had increased levels of leptin, when compared with matched controls. In addition, feeding of fructose to adult offspring revealed that perigestational exposure to HFA renders female progeny more susceptible to developing metabolic unbalance upon such a challenge. The results of this work indicate that perigestational HFA exposure the affects long-term metabolic phenotype of the offspring, predisposing them to an insulin-resistant state.

Maternal folic acid supplementation with vitamin B 12 deficiency during pregnancy and lactation affects the metabolic health of adult female offspring but is dependent on offspring diet

“…One of those studies (16) reported elevated fasting plasma glucose concentrations in adult female offspring Wistar rats from dams fed a diet supplemented with 5 times more folic acid than controls; no effects were observed in the male offspring. Similarly, another study in Sprague-Dawley rats (18) reported that female offspring, but not male offspring, from dams fed a diet supplemented with 20 times more folic acid than controls, had greater weight gain and glucose intolerance. Nonetheless, these findings are similar to what we report here in the control diet-fed, female offspring and in our previous report (23) of no adverse phenotype in adult, male offspring from folic acid-supplemented dams.…”

“…For example, 1 group (20) reported on effects of maternal folic acid deficiency or B 12 deficiency or a combination of both deficiencies in a Wistar rat model and found that male offspring from dams fed the folic acid-or B 12 -deficient diets had greater body weight and adiposity, but glucose tolerance and female offspring were not assessed. Several other groups (16)(17)(18) have reported on effects of maternal folic acid supplementation (with adequate B 12 ) on offspring metabolic health; however, the findings were inconsistent and also vary by animal type and level of folic acid supplementation. Further, most published studies only report on effects in male offspring, with the exception of 2 studies (16,18) that compared male and female offspring.…”

“…Several other groups (16)(17)(18) have reported on effects of maternal folic acid supplementation (with adequate B 12 ) on offspring metabolic health; however, the findings were inconsistent and also vary by animal type and level of folic acid supplementation. Further, most published studies only report on effects in male offspring, with the exception of 2 studies (16,18) that compared male and female offspring. One of those studies (16) reported elevated fasting plasma glucose concentrations in adult female offspring Wistar rats from dams fed a diet supplemented with 5 times more folic acid than controls; no effects were observed in the male offspring.…”

“…Folate and B 12 are metabolically linked; both vitamins are required for the methionine synthase catalyzed remethylation of homocysteine to methionine. Some studies conducted in rodent models have focused solely on investigating the effects of maternal supplementation with just folic acid or supplementation or deficiency of several B vitamins and other methyl donors on offspring body weight and glucose tolerance (15)(16)(17)(18)(19)(20)(21)(22). Most of those studies were conducted only in male offspring, and little is known about the mechanisms underlying the effects of maternal B vitamin status on offspring adiposity and glucose homeostasis.…”

High-dose maternal folic acid supplementation before conception impairs reversal learning in offspring mice

“…In rat offspring, a change in body weight and metabolism as well as an increased risk for mammary adenocarcinomas are associated with high maternal folate levels 9–11 . In mice, disrupted fetal development, embryonic loss, and embryonic developmental delay can be caused by a high-dose FA supplementation in the maternal food during gestation 12, 13 .…”