Peran Micronutrien pada Fetal Programming
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Potential mechanisms of transgenerational developmental programming via maternal (pink) and paternal (blue) lines
FO Programming intervenJon
Maternal line
Oxida6ve stress Epigene6cs Mitochondrial dysfunc6on
F1 phenotype
EpigeneJc germ-‐line
Oocyte mitochondria
EpigeneJc somaJc
F2 phenotype
Paternal line
F1 phenotype
Intrauterine environment
EpigeneJc germ-‐line transmission
microRNA, prions, viruses
F2 phenotype
Further generaJons: propaga6on v directly transmi>ed inheritance Aiken C E , and Ozanne S E Hum. Reprod. Update 2014;20:63-‐75
Factors that directly or indirectly affect fetal development and may thus favour programming of diseases that occur in later life.
Koleganova N et al. Nephrol. Dial. Transplant. 2012;27:3003-3007 © The Author 2012. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail:
[email protected]
Ann Nutr Metab 2011;59(suppl 1):28–42
Clin Epigenet (2011) 2:223–232
Maternal micronutrient deficiency
Hormonal adaptaJons
EpigeneJc gene regulaJon
Fe, Zn, Ca • Increased stress hormones • Decreased somatotrophic hormones (IGF, insulin)
Folate, vitamin B-‐12
Restricted fetal growth and development
Renal funcJon
Fe, Zn, vitamin A, folate • Impaired nephrogenesis / Reduced nephron endowment • Reduced GFR • Increased sodium sensi6vity
Cardiovascular funcJon
Pancreas / β-‐cell funcJon
Fe, Zn, vitamin A, folate
• Impaired vasculariza6on • Malforma6ons • Cardiac hypertrophy
Fe, Zn, folate, vitamin B-‐12 • Reduc6on in number and area of β-‐cells
Hypertension Cardiometabolic risk
Body composiJon
Mg, Zn, Fe, Ca, folate, vitamin B-‐12 • Reduced lean body mass • Altered fat deposi6on or metabolism • Sedentary behavior • Altered appe6te regula6on
Pulmonary funcJon
vitamin A, vitamin D • Reduced bronchial branching & alveoli • Reduced elas6n • Reduced VEGF • Chronic respiratory infec6ons • Reduced lung capacity
Insulin resistance and β-‐ cells dysfuncJon
J. Nutr. 2010; 140: 437–445.
Nutrisi utama pada tumbuh kembang otak janin •
Makronutrien – Protein-‐Energy – Lemak khusus (e.g. LC-‐PUFAs)
•
Mikronutrien – Iron – Zinc – Copper – Selenium, Iodine (Thyroid)
•
Vitamins/Cofactor – B vitamins (B6, B12) – Vitamin A – Vitamin K – Folat – Choline
Mengapa otak membutuhkan besi? 1. Energy 1) Besi dibutuhkan dalam pembentukan ATP di cytochromes 2) Kebutuhan ATP sangat tinggi di janin dan neonatus
2. Neurotransmitters Besi dibutuhkan pada pembektukan dopamine, serotonin, norepinephrine
3. Myelin Enzym yang mengandung besi dibutuhkan pada pembentukan myelin
The role of mircronutrients in brain development
Iron: Metabolic & structural development
Iron: Myelination of neurones
Vitamin B12: Myelination of neurones
Iron: Neurotransmitter function
Zinc: Neuronal replication & synaptogenesis Iodine: Synthesis of thyroid hormones
Vitamin A: Development of visual perception
Choline: precursor for acetylcholine & other compounds
Folic acid: e.g. nucleotide synthesis
Lozoff B et al. Nutr Rev 2006;64:S34–S91 Beard JL. J Nutr 2008;138:2534–2536
Myelina>on of neurons The role of iron in brain development The axon of neurons is covered by myelin, which ‘insulates’ the electrical impulse as it passes through the nerve Myelin is essential for the proper functioning of neurons Myelin is made by oligodendrocytes in the CNS, which are particularly sensitive to iron deprivation1
CNS – central nervous system
1. Beard JL. J Nutr 2008;138:2534–2536
Effect of iron deficiency
Iron deficiency decreases myelin lipids and proteins
Other components of myelination may also be affected, such as myelin compaction
Defects in myelination during early brain development persist into adulthood despite later iron repletion
Data from rat models of brain development
Lozoff B et al. Nutr Rev 2006;64:S34–S91
Luaran Defisiensi Besi Pada Masa Perinatal • Kelainan Perilaku – Rendahnya daya ingat bayi (Siddappa et al, 2004) – Rendahnya tumbuh kembang syaraf pada usia sekolah (Tamura et al, J. Pediatr; 2002)
– Bolot (Riggins et al, Dev Neuropsych, 2009) – Refleks Neurologis Abnormal (Armady-‐Sivan, et al, J Perinatol, 2004).
• Choline pembangun utama sel: – Dibutuhkan pada produksi phospholipids – Dibutuhkan dalam membentuk acetylcholine,suatu neurotransmitter – Dibutuhkan dalam membentuk lipoproteins, nutrisi perantara di seluruh tubuh
• Choline penting pada pembentukan otak dimasa janin dan bayi – choline ibu akan habis jika kebutuhan janin meningkat – Choline peting agar terjadi pertumbuhan tepat pada otak dan sumsum tulang belakang – Choline membantu perkembangan memori dan kognitif – Asupan Choline dibutuhkan dalam jumlah cukup sampai usia 4 tahun, sebagaimana otak terus mebentuk sel baru – Choline menjaga kadar homocystein dibatas normal – Choline mencegah NTD 16
Low choline
Methionine
S-‐adenosylmethionine DNA hypomethylaJon Histone hypomethylaJon
Mitosis DifferenJaJon Apoptosis MigraJon (neurons) Progenitor cells acetylcholine
Low choline during pregnancy
Gene expression
Brain development
CHOLINE phosphocholine
ceramide
methionine
homocysteine
Pyridoxal (Vitamin B6)
PEMT pathway
PhosphaJdylcholine
LysophosphaJdyl-‐ choline
Platelet-‐ acJvaJng factor
dimethylglycine
CDP-‐choline
Sphingomyelin diacylglycerol
betaine
PhosphaJdyl-‐ ethanolamine
Cobalamin (Vitamin B12)
tetrahydrofolate
S-‐adenosyl methionine Amino acid available for
Protein synthesis
dihydrofolate
FOLIC ACID
5-‐methyl-‐ tetrahydrofolate
5,10-‐methylene-‐ tetrahydrofolate
deoxy-‐ pyrimidine base
cysteine
Riboflavin (Vitamin B2)
monomer available for
DNA synthesis and repair
Seminars in Cell & Developmental Biology. 2011; 22(6): 624-‐628
• Telur sumber choline terbaik • Choline berada di bagian kuning telur • Dua buah telur ayam besar mengandung 250 mg choline (setengah kebutuhan ibu hamil) • Telur juga merupakan sumber protein berkualitas tinggi • Telur harganya terjangkau dan mudah didapat dan mudah dimasak
Efek Neurobiologik PUFA • Defisiensi – Mempengaruhi profil asam lemak tubuh – Perilaku abnormal perilaku termasuk pada kecepatan visual
• Efek pada pembentukan syaraf dan otak – Produksi Myelin – Komposisi membran Neuronal – Synaptogenesis
• cell signaling
A
Unified model for the effects of n-‐3 fa_y acids on development of learning memory 18:3n-‐3 ↑ Neuronal differen6a6on
20:5n-‐3 DHA
↑ Neurite outgrowth
PE RXRs signaling
B
↑ Synaptogenesis ↑ Neurogenesis ↑ Neuron protec6on
Unified model for the effects of n-‐3 fa_y acids on maintenance of learning memory 20:5n-‐3 DHA
estrogen
PE RXRs signaling
↑ Synap6c protein expression ↑ long-‐term poten6a6on
↑ Learning memory ↑ Neuron protec6on
↑ Dendri6c spine density
↑ AD preven6on
↑ Synaptogenesis
Reversal of age-‐related changes
↑ Neurite outgrowth ↑ c-‐Fos-‐posi6ve neurons ↑ BDNF ↑ neurogenesis
The Journal of Nutri6onal Biochemistry. 2010; 21(5): 364 -‐ 373
Mengapa Otak membutuhkan Zinc • Berinteraksi di6ngkat DNA (zinc finger proteins) • Diperlukan pembentukan hormon pertumbuhan (IGF-‐1 dan GH) synthesis • Pen6ng pada penglepasan neurotransmi>er • Tumbuh kembang Sistem Syaraf Otonom • Tumbuh kembang daerah Hippocampus (Pusat Belajar dan ingatan
Zinc regulation of neurogenesis.
Levenson C W , Morris D Adv Nutr 2011;2:96-100
©2011 by American Society for Nutrition
Defisiensi Zinc • Janin dari ibu kekurangan Zinc – Menurunnya gerakan janin – Menurunnya variabilitas denyut jantung – Mempengaruhi stabilitas sistem syaraf Otonom
• Postnatal: – Rendahnya daya ingat • Menurunya kemampuan mengobservasi sekeliling • Tidak berhubungan dengan Bayley Mental Developmental Index
Schema6c representa6on of the innate and adap6ve immune system acute response in a normal versus Zn-‐lacking system.
Zinc signaling in zincergic synapses and effect of zinc deficiency.
B R A I N R E S E A R C H R E V I E W S 6 2 ( 2 0 0 9 ) 3 3 – 4 4
Interplay between zinc trafficking, inflammatory signalling and anJmicrobial responses in macrophages
B R A I N R E S E A R C H R E V I E W S 6 2 ( 2 0 0 9 ) 3 3 – 4 4
Consequences of maternal zinc deficiency on birth outcomes and maternal and perinatal health
Am J Clin Nutr 1998;68(suppl):499S–508S
Poten6al links between maternal zinc deficiency and infant postnatal morbidity risk.
Am J Clin Nutr 1998;68(suppl):499S–508S
Interna6onal Journal of Nanomedicine 2011:6 1453–1461
zinc-‐deficient mouse
Supplementation with low doses of RA reduced renal malformations as visualized in E18 fetuses that had undergone prior exposure to a teratogenic dose of RA. The graph shows the percentage of live fetuses with various renal phenotypes (categorized according ...
Lee L M Y et al. PNAS 2012;109:13668-13673
©2012 by National Academy of Sciences
Expression of RaraDN in ureteric bud cells inhibits Ret expression and branching in a dosedependent manner.
Rosselot C et al. Development 2010;137:283-292
RA is sufficient for maintaining Ret expression and branching of isolated ureteric buds in the absence of mesenchyme.
Rosselot C et al. Development 2010;137:283-292
1,500,000 –
Number of glomeruli
Ages 1-17 yrs
In Term Births:
1,000,000 –
Birth Weight Predicts Nephron Number
500,000 –
0 – 2.0 2.5 3.0 3.5
Birth weight, kg 2,000,000 –
Number of glomeruli
All Ages
1,500,000 – 1,000,000 – 500,000 –
Δ ≈230,000 nephrons per kg increase in birth weight ← Hughson et al,
Kid Internat (2003) 63, 2113
0 – 2.0 2.5 3.0 3.5 4.0 4.5 5.0
Birth weight, kg
Also: Merlet-‐Benichou et al, 1999 Manalich et al, 2000
Mechanisms for short-‐ and long-‐term memory.
Trends in Pharmacological Sciences January 2011, Vol. 32, No. 1
A molecular/cellular model of the beneficial role of immune processes in behavioral and neural plasJcity
Brain, Behavior, and Immunity 25 (2011) 181–213
Beef contains large amounts of iron, protein, B6, B12, zinc, and choline
Best-‐known sources of thiamine, foliate and riboflavin. Vitamin B1, B2, B3 and Vitamin C are included in its vitamin content and it is also a rich source of calcium, iron and beta-‐carotene.
The garlic bulb contains high levels of calcium, selenium, potassium, zinc, vitamins B6 and C, manganese and essen6al oils.
NUTRIENT INFORMATION
Amounts per 1 cup (4.86 large eggs) (243g) Calorie InformaJon
Vitamins
Amounts Per Selected Serving Calorie
%DV 347 (1453 kJ)
17%
Amounts Per Selected Serving
%DV
Vitamin A
1183 IU
24%
From Carbohydrate
7,8 (32,7 kJ)
Vitamin C
0,0 mg
0%
From Fat
217 (909 kJ)
Vitamin D
85,1 IU
21%
From Protein
122 (511 kJ)
Vitamin E (Alpha Tocopherol)
2,4 mg
12%
From Alcohol
0,0 (0.0 kJ)
Vitamin K
0,7 mcg
1%
Thiamin
0,2 mg
11%
Riboflavin
1,2 mg
68%
Niacin
0,2 mg
1%
Vitamin B-‐6
0,3 mg
17%
Folate
114 mcg
29%
Vitamin B-‐12
3,1 mcg
52%
Pantothenic Acid
3,5 mg
35%
Choline
610 mg
Betaine
1,5 mg
Carbohydrate Amounts Per Selected Serving
%DV
Total Carbohydrate
1,9 g
1%
Dietary Fiber
0,0 g
0%
Strach
0,0 g
Sugars
1,9 g
Fats & Fa_y Acids Amounts Per Selected Serving
%DV
Total Fat
24,2 g
37%
Saturated Fat
7,5 g
38%
Monounsaturated Fat
9,3 g
Polyunsaturated Fat
3,3 g
Total trans fa>y acids
-‐
Total trans-‐monoenoic fa>y acids
-‐
Total trans-‐polyenoic fa>y acids
-‐
Total Omega-‐3 fa>y acids
180 mg
Total Omega-‐6 fa>y acids
2789 mg
Learn more about these fa>y acids and their equivalent names
Protein & Amino Acids Amounts Per Selected Serving Protein
%DV 30,6 g
61%
Minerals Amounts Per Selected Serving
%DV
Calcium
129 mg
13%
Iron
4,4 mg
25%
Magnesium
29,2 mg
7%
Phosphorus
464 mg
465
Potassium
326 mg
9%
Sodium
340 mg
14%
Zinc
2,7 mg
18%
Copper
0,2 mg
12%
Manganese
0,1 mg
5%
Selenium
77,0 mcg
110%
Fluoride
2,7 mcg
Perbandingan Kandungan Nutrisi telur Bebek dan Ayam Units
Nutrients
DUCK
CHICKEN
Per 100 Grams
Per 100 Grams
Rec Daily Intake
Vitamins mg
Thiamin
0,156
0,062
1,5
mg
Riboflavin
0,404
0,508
1,7
mg
Niacin
0,2
0,073
20
mg
Vitamin B-‐6
0,25
0,139
2
Mcg
Folate
80
47
400
Mcg
Vitamin B-‐12
5,4
1,00
6
IU
Vitamin A, IU
1328
635
5000
64
49
1000
3,85
1,44
18
17
10
400
Minerals mg
Calcium, Ca
mg
Iron, Fe
mg
Magnesium, Mg
mg
Phosphorus, P
220
178
1000
mg
Potassium, K
222
121
4700
mg
Zinc, Zn
1,41
1,1
15
mg
Copper, Cu
0,062
0,014
2
mg
Manganese, Mn
0,038
0,024
2
Mcg
Selenium, Se
36,4
30,8
70
g
Protein
12,81
12,49
50
mg
Cholesterol
884
425
300
Fetal quality Child quality Na6on quality
long-‐term synap6c poten6a6on
