Dissertations, Theses, and Capstone Projects

Date of Degree

9-2024

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biochemistry

Advisor

Xinyin Jiang

Committee Members

Lori Hoepner

Jorge Matias Caviglia

Jia Liu

Louise Hainline

Subject Categories

Biochemical Phenomena, Metabolism, and Nutrition | Biochemistry | Dietetics and Clinical Nutrition | Human and Clinical Nutrition | Maternal and Child Health | Molecular, Genetic, and Biochemical Nutrition | Nutritional and Metabolic Diseases

Keywords

Gestational Diabetes Mellitus, One-Carbon Metabolism Nutrients, Placental Macronutrient Metabolic Genes, DNA Methylation, Children's Growth and Neurodevelopment, Human

Abstract

Maternal insulin resistance and hyperglycemia lead to gestational diabetes mellitus (GDM) which can cause fetal hyperinsulinemia, ultimately leading to excessive fetal growth associated with macrosomia and increased adiposity at birth. Increased placental macronutrient transport and epigenetic changes in growth and metabolic genes affected by GDM contribute to fetal overgrowth and can result in complications such as overweight/obesity, insulin resistance/type 2 diabetes, cardiovascular disease risk factors, as well as cognitive impairment later in life. Choline, an essential nutrient, participates in lipid and energy metabolism by providing methyl groups for DNA methylation and thus may overcome the hypomethylation of growth and metabolic genes affected by GDM. Higher choline intake and availability during GDM pregnancy may alleviate placental macronutrient overflow to the fetus and exert lasting impacts on children’s health via an epigenetic mechanism.

Chapter 1 presents an introduction of current evidence regarding choline’s influence on placental function and subsequent influence on offspring growth outcomes in animal models of GDM.

Chapter 2 presents findings from an observational cohort study regarding maternal choline intake and metabolite status and their associations with placental macronutrient transport and fetal growth outcomes in pregnancies with or without gestational diabetes mellitus. Here we found that maternal choline intakes demonstrated negative associations with several placental macronutrient metabolic genes. The choline metabolite glycerophosphorylcholine (GPC) was associated with reduced placental fat transport and lower birth weight, while free choline was associated with increased fatty acid transport, suggesting choline’s complex role in mediating placental macronutrient transport.

Chapter 3 presents findings on maternal one-carbon metabolism (OCM) nutrient intakes and status and their associations with fetal DNA methylation and altered fetal growth patterns in pregnancies with or without GDM. Here we found that higher maternal choline and betaine intakes may have implications in lower birth weight and fetal stress hormone cortisol levels via an epigenetic mechanism. Further, GDM status may affect the levels of methyl nutrients and DNA methylation but did not modify the association between maternal methyl nutrients and fetal epigenetic marks.

Chapter 4 presents findings on maternal OCM nutrient intakes and status, genotypes, children’s OCM nutrient intake and their associations with anthropometric and neurodevelopment of children at 2 years of age in pregnancies with or without GDM. Here we found that maternal OCM nutrient intakes were negatively associated with children’s weight at 2 years. Some OCM nutrients were also associated with children’s cognitive and language developmental scores. Further, GDM status was associated with lower language developmental scores.

Chapter 5 presents findings on maternal intake and metabolism of lutein and its isomer zeaxanthin (L + Z) and their associations with cognitive development of children at 2 years of age in pregnancies with or without GDM. Here we found that L + Z intake of pregnant women has a positive association with cognitive and language development of children in early childhood. Further, GDM decreased lutein levels in the cord blood, which may suggest the need for higher L + Z intake for women with GDM.

Chapter 6 presents the summary of remaining questions and future directions.

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