micronutrients and developmental programming
TRANSCRIPT
Micronutrients and Developmental Programming
Janina R. W. KavetskyMichigan State University
Animal Science Department
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"
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
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
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
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
One-Carbon MetabolismOne-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)
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
Thin-Fat Indian Phenotype
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
Thin-Fat Indian: Body Fat % vs BMI
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
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
One-Carbon Metabolism and Micronutrients
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
Disease Development: Diabetes
• Genetics
• Fetal Programming• Maternal nutrition• +/- exposure to
endogenous hormones, or endocrine distuptors
SusceptibilityPrecipitating
FactorsAccelerating
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.
Intergenerational Insulin-Resistance-Diabetes Cycle
Exposure to endocrine disruptors
Exposure to endogenous hormones or
excess glucose
Questions????