Zinc, Brain Development

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Zinc,
Brain Development
Performance
Harold H Sandstead, MD
Preventive Medicine Community Health The
University of Texas Medical
Branch Galveston, Texas, USA
October 24, 2002
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Inhibition of Brain Development
Performance
POVERTY
Low maternal education Large Family Poor
Maternal health Maternal growth Maternal
nutrition Obstetrical care
Fetal, neonatal infant malnutrition
Catabolic Illnesses
Social deprivation Environmental inadequacy
In part from Birch Gussow. Disadvantaged
Children. Harcourt, New York, 1970 268.
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Zinc is Essential for Plants

• Aspergillus flavus
• Raulin, 1869
• Maize
• Mazé, 1914 16
• Barley Sunflower
• Somner Lipman, 1926

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Zinc is Essential for Growth
Stunted zinc deficient sunflower normal control
Somner Lipman Plant Phys
19261231-49
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Zinc is Essential for Animals

• Mice
• Hubbel Mendel 1927
• Rats
• Todd et al, 1934
• Swine
• Tucker Salmon, 1955
• Fowl
• ODell et al, 1958

• Humans
• Prasad et al, 1961-3
• Halsted et al, 1972
• Brain Function
• Henkin et al, 1975
• Pregnancy
• Jameson, 1976, 93

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Zinc Deficiency in Egyptian Farmers
Sandstead HH, et al. Am J Clin Nutr
196720422-42.
16 years
16 years
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Zinc Nutriture Birthweight
Dietary zinc lt 6.1 mg was associated with a 2
x?risk of low birth weight (lt 2500 g) in 818 low
SES women from Camden, NJ
Scholl et al. Am. J. Epidemiol. 19931371115-24.
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Risk of Low Birth Weight
Zinc, mg/d by history
Scholl et al Am J Epidemiol 19931371115-24
Odds ratio adjusted for energy, etc
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Importance
FAO data suggest
50 of worlds population
is at risk of Zn deficiency
Brown K, et al Food Nutr Bull 200122113-25
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Estimated Percentage of Population at
Risk of Zinc Deficiency
Brown K, et al Food Nutr Bull 200122113-25
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6-Phosphate Inositol (Phytate)
5 6 phosphate inositols bind Ca, Fe Zn
decrease absorption
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Inhibition of Zinc Absorption by Foods Rich in
Phytate Other Zn Binders
Oyster
120 g frijoles or 120g tortilla inhibited
absorption of Zinc from 120g of oyster
Frijoles
Tortilla
Solomons et al.
J Lab Clin Med 197994335-43
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Concerning the brain, timing of malnutrition
determines adverse effects potential cross
species relationships
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Brain Growth in early Life by Species
Dobbing, 1968
Humans, months
Rats, days
Age
Birth
Age
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Zinc Deficiency Suppresses
Early Gestation

• Preimplantation abnormal embryo development.
  Hurley, 1975
• Low DNA synthesis in neural crest. Swenerton,
  1969
• Abortion, teratology of many tissues. Hurley,
  1966
• Neural tube defects. Hurley, 1972

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Zinc Essential for Embryo Genesis

Normal
Normal
Hurley Shrader. Nature 1975254427-9
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Zinc Deficiency Causes Teratology
Normal
Zinc Deficient
Hurley Swenerton.
PSEBM 1966123692-6.
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Zinc Deficiency Anencephaly in
Humans

• Severe maternal zinc deficiency
  associated with anencephaly.

Hambidge et al. Lancet 19751577-8.
Low maternal plasma zinc concentrations
associated with anencephaly in Turkey.
Çavdar et al. J Tr El Electrolytes Health Dis
198829-14.
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Zinc Deficiency Impairs Growth, Differentiation
Function

• Glutaminergic NMDA calcium channels
• Gene expression
• IGF-1 synthesis
• DNA synthesis
• RNA synthesis
• Protein synthesis
• Function of 100s of enzymes

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Zinc Essential for Glutaminergic NMDA Receptor
Calcium Channels of Cortical Neurons
Browning O'Dell. J Nutr 1994124436-43
19951252083-9
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Calcium Affects Genes via the Enzyme Calcineurin
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Zinc is Essential for DNA Synthesis
Autoradiographic demonstration of 3H-thymidine
incorporation into liver nuclei of normal and
zinc deficient weanling rats. The film showed no
evidence of 3H radiation in the
zinc deficient liver
Normal
Zn Deficient
Sandstead Rinaldi J
Cell Physiol 19697381-3.
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Zinc is Essential for RNA Synthesis
Terhune Sandstead. Science 197217768-9
DNA dependent liver RNA polymerization
did not increase in
Zn deficient suckling rats
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Zinc is Essential for Polysome
Formation Protein Synthesis
Normal
Starved
Fosmire et al. J Nutr 19761061152-8
Zn-
Zinc deficient rat liver had few polysomes.
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Severe Zinc Deficiency in Later Gestation
(day 15-20)

• Fetal stunting, small brain, low cell number.
  McKenzie, 1975
• Behavioral sequellae
• Poor avoidance of shock in males. Halas, 1976.
• Increased aggression in females. Halas, 1975
• Normal maze learning. Halas, 1976

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Avoidance of Shock
Halas, et al. Trace Elem Hum Health Dis 1976 1
327-43.
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Prenatal Zinc Deficiency
Later Avoidance by Adult Male Rats
Halas, et al. Trace Elem Hum Health Dis 1976 1
327-43
Previously zinc deficient offspring performed
poorly.
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Halas, et al. Trace Elem Hum Health Dis 1976 1
327-43
Prenatal Zinc Deficiency
Later Avoidance by Gender
Females performed similar to male controls
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Prenatal Zinc Deficiency Aggression
Halas et al. Nature 1975257221-2
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Prenatal Zinc Deficiency Aggression
Test Chamber
Halas et al. Nature 1975257221-2
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Prenatal Zinc Deficiency Aggression
Halas et al. Nature 1975257221-2
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Prenatal Zinc Deficiency
Aggression in Female Rat Offspring
Halas et al. Nature 1975257221-2
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Severe Postnatal
Zinc Deficiency (day 0-21)

• Low DNA protein synthesis _at_ days 10-11.
  Sandstead, 1972.
• Abnormal histology of cerebellum _at_ 21 days.
  Buell, 1977 Dvergsten, 1983-4.
• Behavioral sequellae
• ?learning. Lokken, 1973.
• ?learning working memory. Halas,
  1983.

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Zinc Deficiency from Birth to Weaning
Normal Control Pair Fed Control Zn
Deficient
Dvergsten et al. Brain Res 1983371217-26.
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Severe Postnatal Zinc Deficiency, Effects on
Cerebellum Maturation was impaired. Division
migration of external granular cell neurons was
suppressed Buell etal.
Exp Neurol 197755199-210.
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Normal Purkinje Cell at 21 Days of Age
Dvergsten et al. Brain Research 1984 31811-20
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Zinc Deficient Purkinje Cell at 21 Days of Age
Dvergsten et al. Brain Research 1984 31811-20
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Postnatal Zinc Deficiency, Birth to
Weaning
Purkinje Cell Dendrites of Normal Rat Pup ?
? Purkinje Cell Dendrites of Zinc Deficient Rat
Pup
Dvergsten et al.
Brain Res 1984318 21-6
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Postnatal Zinc Deficiency Maze Performance
Lokken, et al. PSEBM 1973144680-2
Start
Task after 23h fast rat must run the maze
without entry into side arms. Reward food
pellet. Outcomes time full body errors
total errors.
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Postnatal Zinc Deficiency Maze Performance
Weight
Time
AL
PF
Zn-
Lokken, et al. PSEBM 1973144680-2
Full Body Errors
Total Errors
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Mild Maternal Zn Deficiency from Conception to
Weaning

• Offspring Behavior
  after 100 days
• Histology of Hippocampus after
  200 days

Halas et al. Physiol Behav 198637451-8
Hunt et al. Fed Proc198443382A
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Seventeen Arm Radial Maze for
Testing Spatial Memory
Halas et al. Physiol Behav 198637451-8
Task Retrieve food pellets without
reentering
previously visited arms
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Learning Memory of Female Offspring
Previously zinc deficient rats performed poorly
Zn-
Halas et al. Phys Behav 198637451-8
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Hippocampus of Normal Offspring _at_ 200d of age
Hunt et al. Fed
Proc 198443382A
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Hippocampus of Previously Starved Offspring
_at_ 200d of age. Hunt et al. Fed
Proc 198443382A
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Hippocampus of Previously Zinc Deficient
Offspring _at_ 200d of age. Hunt et
al. Fed Proc 198443382A
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Why does pre /or postnatal zinc deficiency
cause later poor performance neuronal
injury?Hypothesis

• Impairs calcium channels
• inhibits gene expression
• Neurogenesis
• Cell migration
• Synaptogenesis
• Neuronal death
• Etc., etc.

Evidence ?Calcium channels in zinc deficient
neurons
Browning O'Dell. J Nutr 1994124436-43
Browning O'Dell.J. Nutr. 19951252083-9
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Effects of Prenatal Zinc Deficiency in Humans

• Egyptian Infants.
• Kirksey et al. AJCN 199154657-67
• Intrauterine Malnourished Infants
• Ashworth et al. Eur J Clin Nutr 199852223-7

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Human Maternal Zn Status During Gestation
Infant Behavior

• Egyptian infants
• _at_ birth, attention directly related to maternal
  foods rich in zinc.
• _at_ 6 months, infant development inversely related
  to maternal foods low in bioavailable zinc

Kirksey et al. AJCN 199154657-67
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Behavior of Intrauterine Malnourished Infants
after Postnatal Zinc Treatment

• n 205
• Weight 1500-2499 g
• Rx first 8 weeks after birth
• Groups placebo 1 mg 5 mg Zn/d
• Outcomes
• 6-12 months similar mental psychomotor status
  in all groups
• 12 month behaviors most improved after after 5
  mg Zn (plt 0.05)

Ashworth et al. Eur J Clin Nutr 199852223-7
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Conclusions

• Zinc deficiency during brain development causes
  long term sequellae that affect
  neuropsychological functions
• Zinc deficiency during brain development may
  cause premature neuronal death.
• Underlying mechanisms are unknown

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