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5 me Symposium de la Division dendocrinologie, diabtologie et obsit pdiatriques 13 octobre 2016, CHUV Le programming au cours dveloppement: entre environnement et gnome Umberto Simeoni Service de pdiatrie, DMCP CHUV

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Le « programming » au cours développement: entre environnement et génome

Umberto Simeoni Service de pédiatrie, DMCP CHUV & FBM/UNIL Lausanne

5ème Symposium de la Division d’endocrinologie, diabétologie et obésité pédiatriques 13 octobre 2016, CHUV

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Lopez et al, Lancet 2006

The growing burden of noncommunicable diseases (cardiovascular disease,

  • besity, diabetes,…)
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Neonatal Mortality 70%: associated with low birth weight

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Epigenetic Landscape and Biological Development: How the environment affects genes regulation and development

C Waddington

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£ 5.5

  • 6.5
  • 7.5
  • 8.5
  • 9.5

>9.5

Birthweight (pounds)

20 40 60 80 100 120

Standardised Mortality Ratio Men

£ 5.5

  • 6.5
  • 7.5
  • 8.5
  • 9.5

>9.5

Birthweight (pounds)

20 40 60 80 100 120

Women

CORONARY HEART DISEASE Standardised mortality ratios in 10141 men & 5585 women

  • 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

  • f 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

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The amplifying effect of the cycle of reproduction: Worldwide Type 2 Diabetes Mellitus Epidemic

Altered glucose tolerance in offspring Transgenerational transmission Diabetes in pregnancy Increased prevalence of T2DM

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Kidney: Developmental Programming of Hypertension and of Renal Function: Low maternal protein diet, IUGR & effect of postnatal overfeeding (OF)

Systolic ABP 1 month

2 4 6 8

(ml/min/kg)

Control IUGR OF IUGR+OF

CCr 12 months (males)

Boubred et al., Am J Physiol Renal Physiol 2007, 2009

Controls IUGR OF IUGR + OF

Controls IUGR OF IUGR + OF Systolic ABP 4 months Proteinuria 4 months CCr 4 months

*

Glomerular sclerosis

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Hypertension and Renal Damage: Effects of high protein intakes IUGR, Maternal Diabetes

(Inborn nephron deficit)

↓ Filtration surface area ↑ Single nephron

glomerular filtration rate (SNGFR)

↑ Arterial

blood pressure Proteinuria Glomerulosclerosis Glomerular hypertension

RAS

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Glucose tolerance

1 2 3 4 5 t0 t30 t120

insulin (ng/ml)

1 2 3 4 5 t0 t30 t120

glycaemia (g/l)

Glucose tolerance test

Control LP BET

* * * *

*p<0.05

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Developmental « programming » & The Developmental Origins of Health and Disease (DOHaD)

Nutrition, Taste development Microbiome Stress Toxicants Non Communicable Diseases: Hypertension Diabesity Cancer Broncho- pulmonary disease Infertility Neuro-psychic vulnerability, Senescence…

Epigenetic changes: DNA methylation, histones deacetylation/ methylation, phosphorylation, ncRNA Conception 1000 DAYS 2nd birthday Adulthood

Normal variations in nutrition, stress, environmental toxicants exposure, Periconceptional & perinatal disorders and interventions: Preterm birth, Intra-uterine growth restriction, Maternal diabetes/overweight, C-section, ART

2nd hits

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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.

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  • 1800 transcripts altered over 2 X
  • 760 up-regulated
  • 1040 down-regulated

Intrauterine growth restricted (IUGR) neonatal rats: transcriptome analysis

IUGR vs control rats IUGR kidneys

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Epigenetic effectors: IUGR rats

Analysis of specific groups of genes : epigenetic regulators

Buffat et al, PLoS Genet 2011

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Apoptosis and p53 gene methylation In IUGR rat kidney

Pham et al, Am J Physiol 2003;285:R962

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Intergenerational programming

  • f impaired nephrogenesis

Harrisson & Langley-Evans, Br J Nutr 2009

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Peroxysome proliferator activated receptor – a in offspring of rats fed a protein restricted (PR) diet during gestation, prevented by folate supplementation (F)

Adapted from Lillycrop et al, 2005 & Burdge et al 2008 , Gluckman NEJM 2008

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Standard diet (HP diet) 13,0 g/dL (NP diet) 8,7 g/dL D5 D21 D160 G22 J0 IUGR

  • > Postnatal HP diet induces

glomerular hyperfiltration, hypertension and long term glomerular sclerosis

Boubred et al, Pediatr Res 2016

Kidney: Effect of Postnatal High Protein Diet in IUGR Rat Pups

« Pup-in-the cup model »

* * * HP diet *

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High protein intakes in infants

  • Metabolic effects:

– Increased circulating insulin & IGF-1 concentrations, decreased IGF-BP concentrations – Increased branched chain amino acids concentrations

Ziegler et al 2006; Socha et al 2011

  • Renal and cardio-vacular effects:

– Increased renal osmotic load – Glomerular sclerosis

Boubred et al 2007, 2009

 Accelerated growth  Long term insulin-resistance, overweight  Long term altered renal function and structure, hypertension

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Weber et al, Am J Clin Nutr 2014

RCT in the first year of age:

  • Higher protein formula (2.05

followed by 3.2g/dL, up )

  • Lower protein formula (1.25

followed by 1.6g/dL)

  • Breast-feeding (>3 months)

Results at 6 years of age:

Higher protein formula

  • > BMI increased by .51 kg/cm2
  • > Risk for obesity x 2.43

Long term effects of high protein intakes on BMI: CHOP trial

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Fat intakes during infancy

Dietary fat should contribute to 40-60% energy during the first 6 months of life and should decrease gradually to 35% from 6 to 24 months.

FAO, Rome 2010

Diet of 8- to 24-month old children in various industrialized countries contains about 16% energy from proteins and 26-35% from fats; in sharp contrast with the composition of breast milk (low- protein (7%) and high-fat (55%) contents).

Butte et al, J Am Diet Assoc 2010 Uauy & Dangour, Ann Nutr Metab 2009

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Association of nutrition in early life with body fat and serum leptin at adult age

Rolland-Cachera MF et al, Int J Obesity 2012

A 1% increased energy intake from fat at 2 years is associated, at the age of 20 years, with:

lower subscapular skinfold thickness (-2.3% SF, -4.41 to – 0.18, p = 0.03), lower fat mass (-0.31 kg, - 0.60 to – 0.01, p= 0.04) lower serum leptin concentration (0.21 ug/l, -0.39 to 0.03, p= 0.02)

  • Low fat intakes in the first 2 years of life are associated with higher body

fat, particularly at the trunk site and higher leptin concentrations at adult age.

Most children consumed the equivalent of more than four times their protein needs, whereas dietary fat intakes were below current recommendations

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Effects of varying proteins concentrations in infant forumlas

  • n infants weight between 3 and 12 months of age

Patro-Golab et al, J Nutr 2016

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Developmental programming Quelle ampleur d’effet?

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≤67.5

  • 77

>77 0.5 1 1.5 2 2.5 ≤12.4 12.4-13.3 >13.3 Adult weight (kg) Mean L/A ratio Weight at age 2y (kg) p< 0.001

Leptin/adiponectin ratio in young, healthy adults

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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 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

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Conséquences à long terme de la prématurité

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Indicators of Glucose Regulation in VLBW Young Adults

(Hovi et al, NEJM 2007)

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Prevalence of cardio-metabolic complications in adults born preterm

Sipola-Leppanen et al, Am J Epidemiol 2015

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Altered adiposity in adult phenotype of preterm infants

Preterm vs Term Subjects Mean difference/ratio p Total adipose tissue 2.21 L (0.3 – 4.1) 0.03 Abdominal adipose tissue 0.51 L (0.1 – 0.9) 0.007 Systolic blood pressure 6.5 mm Hg (2.2 – 10.8) 0.004 Diastolic blood pressure 5.9 mm HG (1.8 -10.1) 0.006 Intrahepatocellular lipid 3.01 (ratio) (1.78 – 5.28) < 0.001 Tibialis intramyocellular lipid 1.31 (ratio) (1.02 – 1.09) 0.04

Modi N et al Pediatr Res 2011 Greater internal adipose tissue and sinificant urinary metabolome differences in preterm vs term men.

Total body MRI, MRS, urinary metabolomics

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Arterial Blood Pressure in Young Adults Born Preterm Postnatal growth

  • 3
  • 2,5
  • 2
  • 1,5
  • 1
  • 0,5

0,5 1 1,5

Birth 4M 12M 48M 6Y 21Y Z score

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

Growth Systolic blood pressure

53* 89* 69* 122* 112 46 85 65 20 40 60 80 100 120 140 SBP DBP MBP PP Arterial pressure (mmHg)

Preterm Controls

Tauzin et al, JDOHaD 2014

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 altered in vitro angiogenic capacity

  • f low-BW infants cord blood

Endothelial Progenitor Cells

Low birth weight and later hypertension

Cord blood circulating endothelial progenitor cells (ECFC)

NBW LBW

Low BW Controls

Ligi et al, Blood 2011

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 Altered in vivo angiogenic capacity of ECFCs from low birth weight subjects, decreased vascular bed density

Developmentally programmed pathophysiology of hypertension:

Angiogenesis by human cord blood endothelial progenitor cells (ECFCs) implanted in nude mice

Low Birth Weight Controls

Ligi et al, Blood 2011 Frizeira et al, Blood 2014

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Human Cord Blood Endothelial Progenitor Cells Angiogenic Capacity: Maturation of the pro-angiogenic AMOT gene methylation rate

0.00 10.00 20.00 30.00 40.00 50.00 60.00 70.00 26 28 30 32 34 36 38 40 42 Méthylation (%) Age gestationnel (semaines)

CpG 2

0.00 5.00 10.00 15.00 20.00 25.00 30.00 35.00 40.00 26 28 30 32 34 36 38 40 42 Méthylation (%) Age gestationnel (semaines)

CpG 3

0.00 5.00 10.00 15.00 20.00 25.00 30.00 26 28 30 32 34 36 38 40 42 Méthylation (%) Age gestationnel (semaines)

CpG 4

0.00 5.00 10.00 15.00 20.00 25.00 30.00 26 28 30 32 34 36 38 40 42 Méthylation (%) Age gestationnel (semaines)

CpG 5

0.00 5.00 10.00 15.00 20.00 25.00 26 28 30 32 34 36 38 40 42 Méthylation (%) Age gestationnel (semaines)

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)

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SIRT1 decrease correlates with accelerated senescence in Endothelial Colony Forming Cells (ECFCs) from preterm infants

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DNA methylation analysis of the SIRT1 promoter region

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Resveratrol restores SIRT1 expression and cell proliferation in ECFCs

Friseira & Simoncini et al, Blood 2013

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Maternal diabetes: cord blood endothelial progenitors

In vitro hyperglycaemia Intra-uterine diabetic environment

Ingram et al, Diabetes 2008

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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.

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Une prévention précoce ré-orientée vers la période critique de vulnérabilité: les futur-e-s mères et pères et la première enfance

  • Programmes ciblés d’éducation et

information publique, pour la nutrition et style de vie (activité physique, sommeil, addictions)

– en période préconceptionnelle – nutrition et grossesse:

  • prise de poids gravidique
  • supplémentations en micro-nutriments

– dépistage du diabète gestationnel – allaitement maternel et optimisation de la nutrition infantile

  • Réduction du risque d’exposition

aux toxiques et contaminants environnementaux (perturbateurs endocriniens)

  • Approches pharmacologiques

(recherche)

  • globales: modificateurs de la méthylation

(folates)

  • Spécifiques
  • Nécessité de biomarqueurs

précoces

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« We affirm a life-long approach with A focus on the nutrition of women

  • f reproductive age, pregnant women,

nursing mothers and children under five, with particular attention to the first 1000 days from pregnancy to a child’s second

  • birthday. »
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Human genome Genetic variants Human epigenome Health vs Non communicable diseases Periconceptional period 1000 days Life course

Nutrition, lifestyle, stress

Toxicants & environmental disruptors

Innate Acquired