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????