Maternal dietary deficiencies in folates or choline during pregnancy and lactation worsen stroke outcome in 3-month-old male and female mouse offspring

Abstract

Maternal one-carbon (1C) metabolism plays an important role in early life programming. There is a well-established connection between the fetal environment and the health status of the offspring. However, there is a knowledge gap on how maternal nutrition impacts stroke outcome in offspring. The aim of our study was to investigate the role of maternal dietary deficiencies in folic acid or choline on stroke outcome in 3-month-old offspring. Adult female mice were fed a folic acid deficient diet (FADD), choline deficient diet (ChDD), or control diet (CD) prior to pregnancy. They were continued on diets during pregnancy and lactation. Male and female offspring were weaned onto a CD and at 2 months of age were subject to ischemic stroke within the sensorimotor cortex via photothrombosis damage. At 3-months-of-age, motor function was measured in offspring and tissue was collected for analysis. Mothers maintained on either a FADD or ChDD had reduced levels of S-adenosylmethionine in liver and S-adenosylhomocysteine in plasma. After ischemic stroke, motor function was impaired in 3-month-old offspring from deficient mothers compared to CD animals. In brain tissue, there was no difference in ischemic damage volume. When protein levels were assessed in brain tissue, there were lower levels of neurodegeneration in males compared to females and betaine levels were reduced in offspring from ChDD mothers. Our results demonstrate that a deficient maternal diet during critical timepoints in neurodevelopment results in worse stroke outcomes. This study emphasizes the importance of maternal diet and the impact it can have on offspring health.

Maternal Dietary Deficiencies in Folic Acid and Choline Result in Larger Damage Volume, Reduced Neuro-Degeneration and -Inflammation and Changes in Choline Metabolites after Ischemic Stroke in Middle-Aged Offspring

“…There is more compensation at a behavioral level due to the complexity of brain pathways and often times damage and injury can be masked in behavior [ 41 ]. We have previously reported that a deficient diet during pregnancy and lactation impairs motor function in 3-month-old offspring [ 26 ], however, in this study, we show that these effects are only present in brain tissue of middle-aged (11-month-old) offspring and that there is behavioral compensation that occurs after ischemic stroke in both male and female animals. There are still gaps in the literature, and future studies could examine stroke outcomes in aged animals (>18-month-old mice), as well as supplementation with either folic acid or choline after birth.…”

“…The maternal diets in this study consisted of a control diet (CD), folic acid-deficient diet (FADD), and choline-deficient diet (ChDD). The CD represented normal levels of both folic acid and choline that would be found in a conventional diet, which were determined from the previous literature and experimentation [ 24 , 25 , 26 ], both mothers and offspring were fed these diets. The deficient diets consisted of lower levels of folic acid or choline compared to the control diet.…”

Maternal dietary deficiencies in folic acid and choline change metabolites levels in offspring after ischemic stroke

“…Ischemic stroke is a major health concern, with nutrition being a modifiable risk factor. We have previously demonstrated offspring from female mice deficient in either folic acid or choline have worse outcome after stroke (Clementson et al, 2022; Hurley et al, 2023; Pull et al, 2023) . Metabolites are important marker to measure the changes in the gut microbiota, which can be significant markers for different pathophysiological diseases in the body.…”

Maternal dietary deficiencies in one-carbon metabolism during early neurodevelopment result in larger damage volume, reduced neurodegeneration and neuroinflammation and changes in choline metabolites after ischemic stroke in middle-aged offspring

“…There is more compensation at a behavioral level due to the complexity of brain pathways and often times damage and injury can be masked in behavior [45]. We have previously reported that a deficient diet during pregnancy and lactation impairs motor function in 3-month-old offspring [27], however, in this study we show that these effects are only present in brain tissue of middle-aged (11 month old) offspring and that there is behavioral compensation that occurs after ischemic stroke.…”

“…The maternal diets in this study consisted of a control diet (CD), folic acid deficient diet (FADD), and choline deficient diet (ChDD). The CD represented normal levels of both folic acid and choline that would be found in a conventional diet, which were determined from previous literature and experimentation [23,26,27], both mothers and offspring were fed these diets. The deficient diets consisted of lower levels of folic acid or choline compared to the control diet.…”