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Micronutrients and Developmental Programming


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Micronutrients and Developmental Programming

  1. 1. Micronutrients and Developmental Programming Janina R. W. Kavetsky Michigan State University Animal Science Department
  2. 2. Developmental Programming • Developmental plasticity- Ability of an organism to develop in various ways, depending on the particular environment or setting • Developmental programming- Process whereby a stimulus applied in utero establishes a permanent response in the fetus leading to enhanced susceptibility to later diseases • IUGR +/- catchup growth • due to maternal under or over nutrition or exposure to certain substances(e.g. endogenous hormones or endocrine disruptors such as BPs) • impact upon adult health and disease • Commonly associated with cardiovascular and metabolic disorders: • Coronary heart disease and hypertension • Insulin resistance • Obesity • Type 2 diabetes When co- occurring are termed "diabesity"
  3. 3. Developmental Programing: Maternal Undernutrition • Initial evidences from Dutch hunger winter 1944-45 • Dutch population, including pregnant women had to survive on only a few hundred calories/day for many months • Follow-up upon individuals in utero during Dutch hunger winter study • 1st and 2nd trimester fetal undernutrition • Adult obesity • Raised circulating lipids • Blood clotting factors • Increased coronary health risks • Mid, late gestation fetal undernutrition • Impaired renal function • Impaired glucose metabolism Dutch citizens waiting in line for food during the hunger winter
  4. 4. Metabolic Disease and Developmental Programming • Adult type 2 diabetes and/or obesity (Diabesity) related to two factors • NMT Nutrient-mediated teratogenesis • Focuses upon the quality (concentrations of nutrients) of maternal diet during gestation • Deprivation of micronutrients during critical period • FMT Fuel-mediated teratogenesis • Focuses upon quantity of maternal diet during gestation • Excess availability of fuel(glucose) • Diabetic pregnancy • Postnatal availability of excess nutrients in low birth weight infant Teratogenesis= fetal malformations
  5. 5. Developmental Importance of Nutrition • Protein- multiple roles • structure of tissues (muscle, bone, etc.) • transport of molecules, storage and regulation • antibodies, hormones, enzymes, essential amino acids • Essential Micronutrients during Gestation • Vitamin B12-nerve cell health, production of DNA and RNA • Sources: animal products • Folic Acid- proper brain function, also works with B12 for normal red blood cell production • Sources: dark greens • Omega-3 (DHA)•-crucial in brain function, anti-inflammatory, normal growth and development • Sources: fish, oilseed meals • Other key micronutrients • Zinc-cell division, cell growth, wound healing, breakdown of carbs and olfactory senses • Sources :meat, some seafood, legumes, nuts • Iron-normal blood production • Sources: red meat, dark greens • Vitamin D- reduces risks of gestational diabetes, preterm birth, preeclampsia, and infections • Sources: fatty fish (salmon or tuna), fish liver oils, beef liver, eggs
  6. 6. Maternal Protein Intake • Protein restriction during gestation(rodent model) • Decreased pancreatic β- cell mass at birth • Reduced insulin secretion later in life (reduced proliferation and increased apoptosis) • Can lead to the development of diabetes • Rise in hepatic triglycerides • Risk of atherosclerosis • Hepatic expression of lipogenic enzymes • Favor fat synthesis • Excessive fat accumulation • Postnatal food preferences for high fat foods
  7. 7. One-Carbon Metabolism One-carbon Metabolism refers to a group of biochemical reactions involved in amino acid and nucleotide metabolism which involves the transfer of one-carbon groups which are volatile and need to be attached to something while being processed. • Dietary folate is converted to MTFR using B12 as a co-factor • Methylated folate provides methyl groups to convert homocysteine to methionine (universal methyl group donor for all methylation reactions in body)
  8. 8. Maternal B12 Deficiency • Maternal micronutrient restriction • Europeans naturally Folate deficient(dark greens) • Indians typically vitamin B12 deficient (animal products) • Low vitamin B12 level (< 150 pM) • Low birth weight • Adiposity • Insulin resistance • Cardiovascular disease • Poor cognitive performance • Neural tube defects • Hyperhomocysteinemia (biochemical marker for B12 deficit) • CVD morbidity • Dementia • osteoporosis Vitamin B12
  9. 9. Thin-Fat Indian Phenotype • Paternal size will influence skeletal measurements and maternal micronutrient intake will strongly determine fetal size and baby's adiposity • Thin-fat Indian phenotype: • lower birth weight, increased visceral adiposity, altered lipid and glucose metabolism • can increase risk of insulin resistance and diabesity • Strong evidence found in studies of B12 deficiency especially when paired with over availability of folate – PMNS India • Wistar rat model- replicated phenotype of in offspring B12 deficient dams • showed imbalance between pro and anti-inflammatory cytokines • Increased levels of cortisol, and leptin • Decreased levels of adiponectin • Adiponectin -regulation of glucose levels and fatty acid metabolism Indian mother and child with child displaying excess adiposity
  10. 10. Thin-Fat Indian: Body Fat % vs BMI
  11. 11. Maternal Micronutrient Intake • Subclinical micronutrient deficiency in rural Gambia • Vitamin B12, folic acid, Vitamin B6, Vitamin D, selenium, iron, chromium, zinc. • Gambia- nutrition patterns affected by season • Rainy season- low nutrient availability • Long dry season- normal nutrient availability • High incidence of micronutrient deficiency in rainy season • Resultant offspring: • Low birth weight • Childhood morbidity • Childhood mortality Gambian mother and children eating a meal
  12. 12. Prenatal Omega-3 (DHA) • Docosahexaenoic acid (DHA) omega -3 polyunsaturated fatty acids (n-3 PUFA) • DHA has been demonstrated to have role in prevention of insulin resistance and decrease CVD risk (animal models) • DHA availability during perinatal period associated with long term cognitive and visual development • DHA has a critical role in OCM • Altered DHA levels- excess methyl group availability for DNA and histone methylation leading to chromatin remodeling and altered gene expression
  13. 13. One-Carbon Metabolism and Micronutrients
  14. 14. Role of Micronutrients in Omega-3 (DHA) Metabolism • OCM –conversion of folate via B12 coenzyme • produces methionine which is precursor for SAM, methyl group donors from SAM are transferred by PEMT to DHA (also DNA and histones) • Maternal micronutrient imbalance (rat model) • Excess folate and less B12 • influence n-3 PUFA metabolism(OCM) • Decrease plasma and placental DHA levels • Increased placental pro-inflammatory cytokine levels
  15. 15. Disease Development: Diabetes • Genetics • Fetal Programming • Maternal nutrition • +/- exposure to endogenous hormones, or endocrine distuptors Susceptibility Precipitating Factors Accelerating Factors Type 2 Diabetes • Lifestyle • Nutrition • Inactivity • Psychosocial stress • Rapid childhood growth • inflammation • Glucotoxicity • decrease in insulin secretion and an increase in insulin resistance due to chronic hyperglycemia.affects the secretion of β-cells. • Lipotoxicity • metabolic syndrome that results from the accumulation of lipid intermediates in non- adipose tissue, leading to cellular dysfunction and death.
  16. 16. Intergenerational Insulin-Resistance-Diabetes Cycle Exposure to endocrine disruptors Exposure to endogenous hormones or excess glucose
  17. 17. Questions????