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MATERNAL NUTRITION AND
FETAL PROGRAMMING
Kimberly A Vonnahme, PhD Associate Professor Reproductive Physiologist Department of Animal Sciences
North Dakota State UniversityCollege of Agriculture, Food Systems,
and Natural ResourcesFargo, ND 58105-5727
“Healthy Offspring through Optimal Nutrition”
IF MAMA AIN’T
HAPPY,
AIN’T NOBODY
HAPPY
Kimberly A Vonnahme, PhD Associate Professor Reproductive Physiologist Department of Animal Sciences
North Dakota State UniversityCollege of Agriculture, Food Systems,
and Natural ResourcesFargo, ND 58105-5727
“Healthy Offspring through Optimal Nutrition”
ACKNOWLEDGEMENTS
Collaborators at NDSU Joel Caton Christopher Schauer Steve O’Rourke Larry Reynolds Dale Redmer Anna Grazul-Bilska Justin Luther Carrie Hammer Greg Lardy Kasey Carlin Eric Berg
Other collaborators Rick Funston—UNL Bret Taylor—USDA-ARS
SES
Students and Staff Leslie Lekatz Leticia Camacho Erin Harris Allison Meyer Tammi Neville Jim Kirsch Jake Reed
NDSU Animal Nutrition and Physiology Center
OUTLINE
What is Developmental Programming?
What is happening at NDSU?
Nutrient delivery to the fetus
PHENOTYPE
Phenotype = Genotype + Environment
Eg. Milk production = Holstein genetics + Mastitis
Classic Animal Breeding Example
PHENOTYPE
Future Animal Breeding Example
Phenotype = Genotype + Environment Eg. Yield grade = Angus genetics + Uterine environment
PROGRAMMING
The process through which a stimulus or
insult establishes a permanent response
Developmental programming hypothesis
Exposure during a critical period in
development may influence later metabolic
or physiological functions in adult life
“Farmers, ranchers and animal scientists know more about how nutrition affects fertility in cows, pigs and other commercially important animals than fertility experts know about how it affects reproduction in humans. There are small hints scattered across medical journals, but few systematic studies of this crucial connection in people”
DEVELOPMENTAL (FETAL)
PROGRAMMING
Also known as the “Barker Hypothesis”
Dr. David Barker
Clinical
Research
Animal
Research
Epidemiological
Information
THE DUTCH HUNGER WINTER
SEPTEMBER 1944 - MAY 1945
VONNAHME, MARCH 2008
% of babies
who become
obese as adults
0
1
2
3
None1 Last third First two thirds None2
INCIDENCE OF ADULT OBESITY IN
THE CHILDREN OF THE DUTCH
HUNGER WINTER
VONNAHME, MARCH 2008
DEVELOPMENTAL (FETAL)
PROGRAMMING
Also known as the “Barker Hypothesis”
Dr. David Barker
Clinical
Research
Animal
Research
Epidemiological
Information
10 PRINCIPLES OF
DEVELOPMENTAL
PROGRAMMING
1) During development in the womb, there are critical periods of vulnerability to suboptimal conditions.
Vulnerable periods occur at different times for different tissues.
Figure 1. Timeline of bovine fetal development.
The portion in red is the time point of feed
restriction in the current study.
“TIMING IS EVERYTHING”
10 PRINCIPLES OF
DEVELOPMENTAL
PROGRAMMING
5) The placenta plays a key role in programming.
SHEEP AND COW
PLACENTAS
Maternal (caruncular) perfusion
Fetal (cotyledonary) perfusion
COW CAPILLARY DENSITY
C
apill
ary
num
ber d
ensi
ty
0
200
400
600
800
1000
1200
1400
1600
1800
2000
Con CotNR CotCon CarNR Car
Day 125 Day 250
a,bMeans +/- SEM within a day and tissue differ; P<0.01
ab
a,bMeans +/- SEM differ; P<0.01; Vonnahme et al., 2007
VASCULAR FUNCTION
Caruncular Bed, day 125
Epinephrine
1e-9
1e-8
1e-7
1e-6
1e-5
1e-4
1e-3
Cha
nge
from
bas
elin
e, %
-20
0
20
40
60
80
100
120
140
160
180ControlNutrient Restricted
Trt: P = 0.07Dose: P < 0.01T x D: P = 0.92
Vonnahme et al., unpublished data
VASCULAR FUNCTION
Caruncular Bed, day 125
Epinephrine
1e-9
1e-8
1e-7
1e-6
1e-5
1e-4
1e-3
Cha
nge
from
bas
elin
e, %
-20
0
20
40
60
80
100
120
140
160
180ControlNutrient Restricted
Trt: P = 0.07Dose: P < 0.01T x D: P = 0.92
Caruncular Bed, day 250
Epinephrine
1e-9
1e-8
1e-7
1e-6
1e-5
1e-4
1e-3
Cha
nge
from
bas
elin
e, %
-20
0
20
40
60
80ControlNutrient Restricted
Trt: P < 0.01Dose: P < 0.01T x D: P = 0.58
Vonnahme et al., unpublished data
10 PRINCIPLES OF
DEVELOPMENTAL
PROGRAMMING
6) Compensation carries a price. In an unfavorable environment, the developing baby makes attempts to compensate for deficiencies. However, the compensatory effort often carries a price.
?
?
MECHANISMS OF
PROGRAMMING?
Nutritional Influence
Reorganisation of organ structure
Abnormal early cell-cell interactions?
Metabolic Differentiation
DNA Control? (altered cell specific gene regulation)
DNA Environment? (altered DNA binding proteins)
Altered DNA methylation?
Altered Cell Number or
intracellular organization
WHAT’S HAPPENING
AT NDSU?
North Dakota State UniversityCollege of Agriculture, Food Systems,
and Natural ResourcesFargo, ND 58105-5727
“Healthy Offspring through Optimal Nutrition”
NDSU SHEEP STUDIES
High Selenium
(n=42)
Breeding to 50dGA Parturition
(n=14) 100% NRC
(n=14) 60% NRC
(n=13) 100% NRC
(n=14) 60% NRC
Normal Selenium
(n=40)
(n=81) All lambs placed on identical
nutrition scheme until market weight 48 h after birth to weaning =
Bucket Teat Unit Weaning to Market (n=13) 140% NRC
(n=14) 140% NRC
Lamb birth weight
Maternal nutritional intakeRES CON HIGH
Birt
h w
eigh
t, kg
0
1
2
3
4
5 MalesFemales
ab
ac acc
ab
Nut*sex; P = 0.02
EFFECT OF MATERNAL NUTRITION
ON LAMB IgG CONCENTRATION
0
500
1000
1500
2000
2500S
eru
m I
gG
(m
g/d
l)
RES (60%) CON (100%) HIGH (140%)
A Se H Se
Hammer et al., 2011
Nutr. X Se; P < 0.05
EFFECT OF MATERNAL NUTRITION ON
LAMB MORTALITY FROM BIRTH TO
WEANING
0
1
2
3
4
5
6
7
8
9M
ort
ali
ty (
# o
f L
am
bs)
RES (60%) CON (100%) HIGH (140%)
No. of Lambs Hammer et al., 2011
P < 0.02
EFFECT OF MATERNAL NUTRITION ON
COLOSTRUM PRODUCTION IN EWE
LAMBS
0
100
200
300
400
500
600
g o
r m
L
RES (60%) CON (100%) HIGH (140%)
Colostrum Wt. (g) Colstrum Vol. (mL)
Swanson et al., 2008
CON vs. RES, CON vs. HIGH P < 0.01
EFFECT OF MATERNAL NUTRITION
ON TOTAL IgG PRODUCTION
0
5000
10000
15000
20000
25000
30000
35000
40000
45000
Co
lost
ral
IgG
(g
/L)
RES (60%) CON (100%) HIGH (140%)
IgG (mg)
Swanson et al., 2008
CON vs. RES, P = 0.06 CON vs. HIGH; P = 0.06
THE MAMMARY GLAND
HIGH (140% NRC)
MOD (100 % NRC)
LOW (60% NRC)
High Se n = 13 n = 13 n = 11
Adequate Se n = 13 n = 12 n = 14
Nutritional TreatmentsLOW MOD HIGH
Cap
illar
y A
rea
Den
sity
, %
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
0.16
0.18ASeHSe
Se: P < 0.001Nut: P = 0.63Se*Nut: P = 0.51
CAPILLARY AREA DENSITY
VONNAHME, FEBRUARY 2009
Nutrition during
pregnancy impacts on
milk yield
Day postpartum0 2 4 6 8 10 12 14 16 18 20
Milk
yie
ld, g
500
600
700
800
900
1000
1100
60% NRC100% NRC140% NRC
P < 0.001
Selenium during
pregnancy effects on milk
yield
P < 0.001
Days postpartum0 2 4 6 8 10 12 14 16 18 20
Milk
yie
ld, g
500
600
700
800
900
1000
1100
ASeHSe
OTHER POSTNATAL
RESPONSES
Se has positive impacts on carcass traits
Se decreases digestibility
Se increases visceral adiposity
No effect of maternal diet on N retention
No effect of maternal diet on development of the reproductive system
Similar day to puberty
Similar CL proliferation rates
Blood distribution
during pregnancy
Uteroplacental blood flow increases dramatically to support the nutritional demands of the rapidly growing fetus
Increased maternal plasma volume
30 to 40% increase
Increased maternal cardiac output
35% increase in stroke volume
15% increase in heart rate
Fractional distribution of cardiac output to the uterus
% of Cardiac Output
0.5% non-pregnant
>16% late pregnant
Note: the % of cardiac output delivered to the other tissues falls, however, absolute values of blood flow are unchanged, further pointing to the need for an expanded blood volume
Rosenfeld, 1984
Nourishing the
uteroplacenta
Uterine blood flow is increased during pregnancy
Vasodilatation
Vascular remodeling
Caruncular
Cotyledonary
Day 50 Day 140
•Fetal (Cotyledonary) Vascularity: – Capillary area density (6.2X) – Capillary no. density (12.3X) – Cap. surface density (6.0X) – Area per capillary (1.9X)
•Maternal (Caruncular) Vascularity: – Capillary area density (3.3X) – Capillary no. density (1.5X) – Cap. surface density (1.7X) – Area per capillary (2.2X)
DOPPLER ULTRASONOGRAPHY
METHODS
Fetal heart rate
Pulsatility index (PI) = PSV – EDV Mean Velocity
Resistance index (RI) = PSV – EDV PSV
Angle of insonation
Diameter of vessel
90
45
PATIENCE AND TIME
REALIMENTATION WILL INCREASE
UTERINE BLOOD FLOW
100%
(n=18)
100% (n=6)
60% (n=6)
60% (n=6)
100%
100%
60%
100%
d 0 d 30 d 85 d 140 d 260
Percentage NRC recommendations
5/22/2012
UTERINE ARTERIAL
RESISTANCE
Day of gestation
30 44 58 72 85 100
114
128
140
156
170
184
198
212
226
240
254
Resis
tan
ce in
dex
0.60
0.65
0.70
0.75
0.80
0.85CCCRCCRRC
SEMTrt, P < 0.001Day, P < 0.001Trt*day, P = 0.460.0
0.2
0.4
0.6
0.8 a a b
GLOBAL NUTRITION
Maternal intake and BW
changes
Day of gestation40 60 80 100 120 140 160
Wei
ght,
kg
45
50
55
60
65
70
75
8060% NRC100% NRC140% NRC
*Se – NS Diet – P<0.01,
(d90-145, all diets differ)
Lamb birth weight
Maternal nutritional intakeRES CON HIGH
Birt
h w
eigh
t, kg
0
1
2
3
4
5 MalesFemales
ab
ac acc
ab
Nut*sex; P = 0.02
Umbilical Blood Flow in
Pregnant Ewes
RES CON EXCC
han
ge i
n R
I, %
-20
-15
-10
-5
0
5
10
15P = 0.01a
b
ab
Lekatz et al., 2009
PROTEIN SUPPLEMENTATION
DURING LATE PREGNANCY
Impacts on female progeny reproductive success
3 yrs: Gudmundsen Sandhills (n=170 heifer calves)
Cows bred
No supplement (NoProt)
Protein (Prot) 0.45 kg/d 42% CP
12/1 – 2/28 LG
3 yrs: Gudmundsen Sandhills (n=170 heifer calves)
Cows bred
No supplement (NoProt)
Protein (Prot) 0.45 kg/d 42% CP
12/1 – 2/28 LG Ave calving date =March 27
REPRODUCTIVE PERFORMANCE
Treatment
Item Prot NoProt SEM P-value
Age at Puberty, d 339 334 10 0.70
Cycling at beginning of breeding
season, % 61 67 - 0.45
Calved in first 21 d, % 77 49 - 0.005
Overall pregnancy rate, % 93 80 - 0.05
Calving date, Julian d 71 75 3 0.15
Calf birth wt, kg 33 33 1 0.94
Unassisted births, % 78 64 - 0.24
REPRODUCTIVE PERFORMANCE
Treatment
Item Prot NoProt SEM P-value
Age at Puberty, d 339 334 10 0.70
Cycling at beginning of breeding
season, % 61 67 - 0.45
Calved in first 21 d, % 77 49 - 0.005
Overall pregnancy rate, % 93 80 - 0.05
Calving date, Julian d 71 75 3 0.15
Calf birth wt, kg 33 33 1 0.94
Unassisted births, % 78 64 - 0.24
REPRODUCTIVE PERFORMANCE
Treatment
Item Prot NoProt SEM P-value
Age at Puberty, d 339 334 10 0.70
Cycling at beginning of breeding
season, % 61 67 - 0.45
Calved in first 21 d, % 77 49 - 0.005
Overall pregnancy rate, % 93 80 - 0.05
Calving date, Julian d 71 75 3 0.15
Calf birth wt, kg 33 33 1 0.94
Unassisted births, % 78 64 - 0.24
CONTROL DIET (n = 10)
CONTROL DIET (n = 5)
CONTROL DIET +
SUPPLEMENT (n = 5)
d 180 US Begins
CAN MELATONIN SPARE
FETAL WEIGHT LOSS?
CAN MELATONIN SPARE
FETAL WEIGHT LOSS?
LEMLEY ET AL., 2011
Day 130
ADQ (n = 31) CON-RES (n = 8)
Day 0 Day 50
CON-ADQ (n = 7)
MEL-ADQ (n = 8)
MEL-RES (n = 8)
40 50 60 70 80 90 100 110
Um
bil
ical
BF
, m
L/m
in
0
100
200
300
400
500CON-RES (n = 8)CON-ADQ (n = 7)MEL-RES (n = 8)MEL-ADQ (n = 8)
Trt*Nut*Day; P = 0.15
40 50 60 70 80 90 100 110
Um
bil
ical
BF
, m
L/m
in
0
100
200
300
400
500CON (n = 15)MEL (n = 16)
Trt*Day; P < 0.001
*
*
*
*
**
Gestation, d
40 50 60 70 80 90 100 110
Um
bil
ical
BF
, m
L/m
in
0
100
200
300
400
500ADQ (n = 15)RES (n = 16)
Nut*Day; P < 0.0001
*
*
*
*
40 50 60 70 80 90 100 110
Um
bil
ical
BF
, m
L/m
in
0
100
200
300
400
500CON-RES (n = 8)CON-ADQ (n = 7)MEL-RES (n = 8)MEL-ADQ (n = 8)
Trt*Nut*Day; P = 0.15
40 50 60 70 80 90 100 110
Um
bil
ical
BF
, m
L/m
in
0
100
200
300
400
500CON (n = 15)MEL (n = 16)
Trt*Day; P < 0.001
*
*
*
*
**
Gestation, d
40 50 60 70 80 90 100 110
Um
bil
ical
BF
, m
L/m
in
0
100
200
300
400
500ADQ (n = 15)RES (n = 16)
Nut*Day; P < 0.0001
*
*
*
*
DON’T JUST BLAME YOUR MOM!
Research studies performed in rodents
Drugs
Carcinogens
Environmental estrogens (BPA)
Conclusions: Dad can impact fetal development
Work in livestock is largely lacking
FUTURE DIRECTIONS
Time period of supplementation
Specific nutrients that are important
Maternal efficiencies
Factors that impact uterine and placental blood flow
Developmental
Programming
IMPORTANT TO ANIMAL HEALTH AND PRODUCTIVITY:
Growth and nutrient transfer
Reproductive capacity
Aging and lifetime productivity
GOAL: HEALTHY OFFSPRING!!!
VONNAHME, MARCH 2008
ACKNOWLEDGEMENTS
NDSU Animal Nutrition and Physiology Center
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