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 one-carbon metabolism, including dietary levels of folic acid and choline, play an important role in early life programming. There is a well-established connection between the fetal environment and the health status of offspring. However, there is a gap in knowledge on how maternal nutrition will affect the health status of the offspring after a cardiovascular event like ischemic stroke. The aim of our study was to investigate the role of maternal dietary deficiencies in folic acid or choline on stroke outcome in 3- and 10-month-old male and female offspring. Adult female mice were fed a folic acid deficient diet (FADD), a choline deficient diet (ChDD), or a control diet (CD) four weeks prior to pregnancy to deplete stores, they were continued on diets during pregnancy and lactation. Male and female offspring were weaned onto a control diet and at 2 or 10 months of age were subject to ischemic stroke within the sensorimotor cortex via the photothrombosis ischemic damage model. At 3 or 11 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 tissue compared to controls. In offspring after ischemic stroke, motor function was impaired in 3-month-old male and female offspring from deficient mothers compared to control diet offspring. In 11-month-old mice there was no impact of maternal diet on motor function, but we observed sex differences. Male middle-aged adult mice had worse motor function compared to female offspring. In brain tissue, there was no impact of maternal diet on ischemic damage volume in 3-month-old animals. Interestingly, maternal diet impacted ischemic damage in 10-month-old male and female offspring. Neurodegeneration and choline metabolism in ischemic brain tissue was also impacted in 3 and 11-month-old offspring. The findings of our study suggest that a maternal diet deficient in either choline or folic acid impacts stroke outcome in young animals compared to middle-aged animals. These results points to the important role of the maternal diet in early life programming, while emphasizing its effects on both fetal development and long-term cerebrovascular health.
Ischemic stroke is an unmet medical need within the clinical population and is associated with significant mortality and morbidity. Nutrition is a modifiable risk factor for ischemic stroke. A maternal diet that provides adequate nutrition during pregnancy and lactation is vital to the neurodevelopment of offspring. Deficiencies in nutrients during fetal growth can lead to altered early life nutritional programming, such as spina bifida, a neural tube defect. There is an opportunity for advancing therapeutic intervention by completing additional research aimed at understanding the mechanistic impact of maternal nutrition on offspring ischemic stroke. Dietary deficiencies of one‐carbon (1C) metabolites have been associated with an increased risk for stroke. 1C metabolites include folic acid and choline which play a vital role in early life neurodevelopment. Data from our laboratory demonstrates that maternal dietary deficiencies in these vitamins and nutrients impact stroke outcome in 2‐month‐old male and female offspring, however, the mechanisms through which this occurs remain unknown. The aim of the present study was to investigate the impact of maternal dietary deficiencies in folic acid or choline on neuronal viability. This project used hypoxia as an in vitro model of stroke. Prior to mating, female mice were placed on a control, folic acid, or choline deficient diet for 4 weeks. Primary neurons were isolated from embryonic tissue, grown in culture, and exposed to hypoxia, after which cells were returned to normoxia. Twenty‐four hours after hypoxia, neuronal viability and apoptosis was measured in cultures. Our results demonstrate that offspring neurons from deficient mothers had reduced cell viability. There was also a change in the level of apoptosis between maternal dietary groups and treatments. These results suggest that a maternal dietary deficiency during pregnancy negatively impacts neurons after hypoxia.
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