Epigenetics and pregnancy
Umberto Simeoni Division of Pediatrics & DOHaD Lab
CHUV & FBM/UNIL Lausanne, CH
EGEA 8th Conference Nutrition and Health: From science to practice Lyon, November 7-9th, 2018
Trends in the number of adults with diabetes by region 1980-2014
Non Communicable Diseases Risk Factor Collaboration, Lancet 2016
Global map of mean birth weight (WHO)
Epigenetic Landscape and Biological Development: How the environment affects genes regulation and development
C Waddington
The effect of finite periods of undernutrition at different ages on the composition
and the subsequent development of the rat Widdowson & Mc Cance, Proc. Roy Soc London 1966
The effect of birth weight on the mortality ratio of coronary heart disease in human
Barker et al, Lancet 1989
Developmental programming: A process by which a stimulus applied during a criticial period of sensitivity during development exerts not only short term, but lifelong effects
Lackland BT et al. Arch Intern Med 2000, adapted
Birth Weight vs Chronic Renal Failure
Case-control study Patients = 1230 Controls = 2460
Effect size of developmental programming: prevalence of hypertension
Birth -weight
(kg)
%
Fifths of current weight (kg)
-74.8 -62.6
-81.5 -68.7
-88.0 -75.2
-96.5 -83.9
>96.5 >83.9
M F
M F
0
20
40
60
80
>4.0
-4.0 -3.5
-3.0
Barker DJ, Osmond C, Forsen TJ, Kajantie E, Eriksson JG. N Engl.J Med. 2005;353:1802-9
Epigenetics: a long lasting, heritable molecular translation of early genome-environment interactions, in the absence of gene sequence alteration
Non coding RNAs
Royal gelly fed bees
become bigger, live longer and are fertile.
The Developmental Origins of Health and Disease (DOHaD)
Gene expression Organ/system function and structure
Behavioural and environmental sensitivity
Inheritable acquired traits: DNA methylation Histones modifications ncRNAs
Worldwide Type 2 Diabetes Epidemic: the amplifying effect of the cycle of reproduction
Altered glucose tolerance and overweight/obesity in offspring
Intergenerational transmission
Overweight/Obesity Diabetes/Hyperglycaemia in pregnancy
Overweight/Obesity Increased prevalence of T2DM
The long term memory of early environmental cues
Early nutrition & environment
Epigenetic imprinting
Microbiome
Long term or chronic disease (diabetes, obesity, hypertension,…)
Gut immune system Low grade inflammation SCFA (butyrate) Metabolism
Intra-uterine Growth Restriction, Preterm birth, or Antenatal exposure to Hyperglycaemia in pregnancy Common long term complications in offspring and common programming mechanisms
• Hypertension & cardio-vascular disease
Reduced nephron endowment Altered endothelial function
• Impaired angiogenesis • Altered endothelium-dependent vasodilating capacity
(IUGR, DIP) • Arterial stiffness, Intima-media thickness
• Impaired Glucose Tolerance, Type 2 Diabetes
Mellitus,
Reduced insulin sensitivity Insufficient insulin production Obesity (IUGR, DIP)
Arterial Blood Pressure in Young Adults Born Preterm
vs Postnatal Growth
-3
-2,5
-2
-1,5
-1
-0,5
0
0,5
1
1,5
Birth 4M 12M 48M 6Y 21Y
Z sc
ore
Preterm, height Control, height
Preterm, weight Control, weight
Systolic blood pressure correlations
r p
Change in Z-score for weight (4-12 months)
0.426 0.048
Weight gain : 6-21 years (absolute)
0.419 0.03
Weight gain : 6-21 years (relative)
0.582 0.001
Change in Z-score for weight (6-21 years)
0.381 0.05
Change in BMI (6-21 years) 0.489 0.011
122*
69*
89*
53*
112
65
85
46
0
20
40
60
80
100
120
140
SBP DBP MBP PP
Art
eria
l pre
ssur
e (m
mH
g)
Growth Systolic blood pressure
Preterm
Controls
Tauzin et al, JDOHaD 2014
Altered angiogenesis in preterm infants: SIRT1 decrease correlates with accelerated senescence in Endothelial Colony Forming Cells (ECFCs)
Ligi et al, Blood 2011 Frizeira-Vassallo et al, Blood 2014
Human Cord Blood Endothelial Progenitor Cells Angiogenic Capacity: Maturation of AMOT gene methylation rate
0,00
50,00
100,00
26 28 30 32 34 36 38 40 42
Mét
hyla
tion
(%)
Age gestationnel (semain
CpG 2
0,0010,0020,0030,0040,00
26 28 30 32 34 36 38 40 42Mét
hyla
tion
(%)
Age gestationnel (semaines)
CpG 3
0,00
10,00
20,00
30,00
26 28 30 32 34 36 38 40 42
Mét
hyla
tion
(%)
Age gestationnel (semaine
CpG 4
0,00
10,00
20,00
30,00
26 28 30 32 34 36 38 40 42
Mét
hyla
tion
(%)
Age gestationnel (semaine
CpG 5
0,00
10,00
20,00
30,00
26 28 30 32 34 36 38 40 42
Mét
hyla
tion
(%)
Age gestationnel (semaine
CpG 6
-1.5092(P=4e-02) -1.3592(P=8.3e-04) -0.9947(P=6.4e-04)
-0.8804(P=3.1e-04) -0.4616(P=1.6e-02)
Gestational age (wks)
Gestational age (wks) Gestational age (wks)
Gestational age (wks) Gestational age (wks)
Vinci et al, PLoS One, 2017
Maternal Low Protein Diet during Gestation (IUGR) + Postnatal Overfeeding during Lactation (OF):
Offspring Systolic Blood Pressure (SBP)
50
75
100
125
150
175
1M 2M 4M
SBP
(mm
Hg)
Control IUGR OF IUGR+OF
* *
* * * * *
M = Age in Months
Boubred et al, AJP 2007; 2009
Graph2
Feuil1
NPLPOFLP+OF
1M110117116127
2M130144146145
4M135146148149
12M125128136140
3232
331.62
2343.5
2.51.567
Feuil1
33331.61.622
��������
2233443.53.5
��������
��������
��������
2.52.51.51.56677
NP
LP
OF
LP+OF
2 4 12 Months
SBP (mmHg)
Feuil2
22332233
221.61.63333
��������
3.53.5443322
��������
��������
��������
77661.51.52.52.5
LP+OF
OF
LP
NP
1 2 4 12 Months
SBP (mmHg)
Feuil3
Seasonal variation of methylation of metastable epialleles in infants according to maternal nutrition at conception in Gambia
Peripheral blood lymphocytes
Hair follicles
Dominguez-Salas P et al, Nature 2014
Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice
Gapp et al, Nature Neurosci 2014
Behavioral and metabolic responses in “unpredictable maternal separation combined with unpredictable maternal stress” (MSUS) males across generations and in mice derived from RNA-injected oocytes.
Dad is having a much larger role in the whole process, rather than just delivering his genome and being done with it.
Early nutrition, Toxicants,
Taste Behavior
Microbiota
Developmental Programming & Developmental Origins of Health and Disease (DOHaD)
Preterm birth IUGR
Maternal diabetes/
overweight C-section birth
Infection Hypo-hyperoxia
Pre- and peri-conceptional environment:
parental nutrition, lifestyle, toxicants,
ART
Epigenetic changes
Stress, Behavior, Senescence
Conception 1000 DAYS 2nd birthday Adulthood
Normal environmental variations (nutrition, stress) Non Communicable Diseases:
Hypertension Diabetes, Obesity
Broncho-pulm. Neuro-psych.
Cancer Infertility
Senescence Social vulnerabilty
Microbiome
Ma RW, Armengaud JB, et al, Diabetes Res & Clin Pract, 2018
Lifecourse approach to NCDs prevention
DOHaD Lab & Divisions of Pediatrics CHUV & FBM/UNIL, CH-
Lausanne
• H Chehade • J-B Armengaud • C Yzydorczyk • U Simeoni
• B Siddeek • M Benahmed (INSERM-U895,
Nice)
Cooperation: • Neonatology Lab, CHUV (J-F Tolsa,
M Roth-Kleiner, A-C Peyter, S Gremlich)
• MRC Lifecourse Souhtampton (C Osmond)
• Heart Research Center, Portland (K Thornburg)
• INSERM 866 Dijon (C Vergely) • INSERM 1076 Aix-Marseille
University (F Dignat-George)
Cardio-vascular, Metabolic Kidney, Immune System, Nutrition, Oxydative stress Senescence
Reproduction, Cancer Epigenetics, ncRNA
Diapositive numéro 1Trends in the number of adults with diabetes by region 1980-2014Global map of mean birth weight (WHO)Epigenetic Landscape and Biological Development:�How the environment affects genes regulation �and developmentDevelopmental programming:� �A process by which a stimulus applied during a criticial period of sensitivity during development exerts not only short term, but lifelong effectsBirth Weight vs Chronic Renal FailureEffect size of developmental programming: prevalence of hypertensionEpigenetics: a long lasting, heritable molecular translation of early genome-environment interactions, in the absence of gene sequence alterationThe Developmental Origins of Health and Disease (DOHaD)Worldwide Type 2 Diabetes Epidemic:�the amplifying effect of the cycle of reproductionThe long term memory of early environmental cuesIntra-uterine Growth Restriction, Preterm birth, �or Antenatal exposure to Hyperglycaemia in pregnancy��Common long term complications in offspring�and common programming mechanismsArterial Blood Pressure in�Young Adults Born Preterm�vs Postnatal GrowthAltered angiogenesis in preterm infants: �SIRT1 decrease correlates with accelerated senescence in Endothelial Colony Forming Cells (ECFCs)Diapositive numéro 16Maternal Low Protein Diet during Gestation (IUGR)�+ Postnatal Overfeeding during Lactation (OF):�Offspring Systolic Blood Pressure (SBP)Seasonal variation of methylation of metastable epialleles in infants �according to maternal nutrition at conception in GambiaDiapositive numéro 19Diapositive numéro 20Diapositive numéro 21Diapositive numéro 22DOHaD Lab & Divisions of Pediatrics CHUV & FBM/UNIL, CH-Lausanne
