1

Developmental Origins of

Health and Disease: from

concepts to interventions

Mark Hanson

United Nations (Sept 2011): Political declaration of the High-level Meeting of the General Assembly on the Prevention & Control of Non-communicable Diseases

14. In 2008, an estimate 36 million of the 57 million global deaths were due to NCDs, .... and that nearly 80% of those deaths occurred in developing countries

26. {We} note also with concern that maternal and child health is inextricably linked with NCDs and their risk factors, specifically as prenatal malnutrition and low birth weight create a predisposition to obesity, high blood pressure, heart disease and diabetes later in life; and that pregnancy conditions, such as maternal obesity and gestational diabetes, are associated with similar risks in both the mother and her offspring

37. Acknowledge the contribution and important role played by all relevant stakeholders, including individuals, families, and communities, intergovernmental organizations and religious institutions, civil society, academia, media, voluntary associations, and where and as appropriate, the private sector and industry, in support of national efforts for NCD prevention and control

Consequences of childhood obesity. From Han et al (2010) Lancet

375:1737-45

Lifecourse view of NCD risk

Plasticity

Life course

No intervention

Mother

& infant

Earlier intervention

improves functional

capacity & responses

to new challenges

Inadequate response

to new challenges

Childhood &

adolescence

Adulthood

Early intervention

Late intervention

Late intervention has

impact for

vulnerable groups

Sumithran et al NEJM (2011) 365: 1597-604

The Metabolic Syndrome

7

Juonala et al.

(2011) NEJM

365:1876- 85

Thin child, thin adult

Fat child, thin adult

Fat child, fat adult

Thin child, fat adult

Children:

11.4 + 4.0 yr

Adults:

23.1 + 3.3 yr later

“Mismatch”

Modified from Gluckman PD, Hanson MA (2004) Science 305 (5691):1733-6

Ad

ult

En

vir

on

men

t

Healthy

range

Mismatch concept

Animal models

• Obesity

• Reduced muscle mass

• Reduced bone density

• Fatty liver

• High blood pressure/ vascular dysfunction

• Insulin and Leptin resistance

• Altered appetite/ hyperphagia/ fatty food preference

• Altered stress hormones/ anxiety

• Reduced learning

• Earlier puberty

Rat – mother fed an unbalanced diet (protein/ carbohydrate/ fat) during

pregnancy, and offspring fed an adequate or excessive diet (“mismatched”)

This produces a range of health problems in adulthood, similar to human

disease

0

2

4

6

8

10

12

14

16

Hum

an

Guine

a pig

Har

p se

al

Fur sea

l

Sea

Lions

Rei

ndee

r

Bab

oon

Lam

bCal

f

Foal

Black

bea

r

Mou

se

Eleph

ant s

eal

Rab

bit

Cat

Car

ibou P

igRat

Ham

ster

% b

od

y f

at

Our normal biology: of all mammals,

we are the fattest at birth.

The Importance of Prospective studies – e.g.

Southampton Women’s Survey (SWS)

Population of 12,500 non-pregnant Southampton women aged 20-34 years interviewed about diet, physical activity, social circumstances & lifestyle;

body fatness measured; DNA & blood samples taken.

3150 pregnancies studied

Ultrasounds at 11, 19, 34 wks

Interviews at 11 & 34 weeks

Maternal grandparents’ DNA

Maternal blood samples

Paternal DNA & blood

Neonatal size & thinness/fatness;

cord blood; placental samples

Offspring home visits at 6, 12, 24 & 36 months. Clinic/home visits at 4, 6 & 8 years

Median times per week food is consumed

in the least and most ‘prudent’ diet

quarters Food Least prudent Most prudent

Sugar 21 0

White bread 14 3

Red meat and processed meat

7 2

Crisps and confectionery

10 4

Fruit and fruit juice 7 18

Non-salad vegetables

9 17

Salad vegetables 3 11

Fetal liver blood flow has long-

term implications for liver metabolism,

growth factor production

and fat deposition

What processes

influence fetal fat

deposition?

Haugen et al (2005) Circulation Research

96(1): 12-4

Mother’s diet before pregnancy

110

130

150

170

190

< -0.44 - +0.11 - +0.75 > +0.75

Less prudent More prudent

Pre-pregnant dietary prudence

Total liver flow

r=-0.15, P=0.03

“less prudent diet” low fruit / vegetables, high red

meat / white bread / sugar / crisps

15

20

25

30

< -0.44 - +0.11 - +0.75 > +0.75

Ductus venosus shunting

r=0.17, P=0.01

% D

uct

us

ven

osu

s sh

un

tin

g

Less prudent More prudent

Pre-pregnant dietary prudence

Haugen et al (2005) Circulation Research 96(1): 12-14

Godfrey KM et al PLoSOne

Which tissues are available for

epigenetic analysis?

Candidate gene pathways involved

3.0

4.0

5.0

6.0

7.0

8.0

2-35% -59% -84% -100%

Degree of epigenetic change in one CpG in RXRa gene

Values are means + SEM

PAH study children

aged 9 years

Epigenetic state at birth predicts body composition in childhood

3.0

4.0

5.0

6.0

7.0

8.0

-63% -73% -80% -100%

SWS children

aged 6 years

Godfrey et al 2011 (Diabetes 60: 1528- 1534)

Diet in pregnancy & ponderal index at birth 538 term Southampton pregnancies

Carbohydrate intake in early pregnancy

(g/day)

Dairy protein intake in late pregnancy

(g/day)

Carbohydrate P=0.01 Dairy protein P=0.03

Godfrey et al BJOG 1997;104:663-7

r=-0.26, P=0.027,

n=64

Maternal carbohydrate intake

in early pregnancy (quartiles)

Epigenetic change in

RXRa gene

Low maternal carbohydrate intake in early pregnancy

associated with higher umbilical cord RXRA gene

promoter methylation

40

50

60

70

80

Lowest 2nd 3rd Highest

N.B. No

association

with mother’s

BMI or

offspring

birthweight

Godfrey et al 2011 (Diabetes 60: 1528- 1534)

DNA Methylation Patterns in Cord Blood DNA

and Body Size in Childhood

PLoS ONE March 2012 | Volume 7 | Issue 3 |

e31821

Modified from Gluckman PD, Hanson MA (2004) Science 305 (5691):1733-6

Ad

ult

En

vir

on

men

t

Healthy

range

Epigenetic

processes try

to achieve

match

Mismatch concept

Chan LL, Lau WL, Leung WC

C-C C-HF HF-HF HF-C0

10

20

30

40

tota

l bo

dy fat

(as %

bo

dy w

eig

ht)

Female offspring of mice exposed to a high fat (HF)

diet from weaning, through pregnancy and suckling

+/- HF diet after they were weaned

Fat deposition in liver

Elahi et al 2009

let - 7c

ppar - a

Igf2

Maternal HF diet

miR - 122

cpt - 1a

FFA

Fatty acid oxidation

Hepatic growth

CHD4

DOT1L

HIC2

PDGFB

miR - 494 CS?

Igf1R?

miR - 709

MECP2?

miR - 503*

miR - 770 - 3p

miR - 369 - 3p

miR - 197

miR - 667

Hist4H4?

MBD6?

miR - let - 7s

miR - 122

miR - 194

miR - 26a

let - 7c

- a

Igf2

Maternal HFdiet

miR - 122

cpt - 1a

FFA

Fatty acid oxidation

Hepatic growth

CHD4

DOT1L

HIC2

PDGFB

miR - 494 CS?

Igf1R?

miR - 709

MECP2?

miR - 503*

miR - 770 - 3p

miR - 369 - 3p

miR - 197

miR - 667

Hist4H4?

MBD6?

miR - let - 7s

miR - 122

miR - 194

miR - 26a

Zhang et al BMC Genomics. 2009 16;10:478.

Patterns of miRNA expression

0

5

10

15

20

25

30

35

<18.5 18.5-24.9 25-29.9 30-39.9 >40

Maternal BMI

Ob

es

ity

(%

of

ch

ild

ren

)

What is “abnormal”?

Obesity (BMI ≥ 95th percentile) at age 4 years according to

maternal first-trimester BMI

From Whitaker, Pediatrics. 2004 Jul;114(1):e29-36.

p < 0.001

Bouchard L et al Diabetes 6 March 2012

Other demographic changes

• Falling family size

• Rising maternal age

• Higher rate of caesarean

sections

Interaction between parity and mother’s body

composition mean % body fat from skinfold thickness

in 276 men & women aged 28-31 years

25.0

30.0

35.0

-21.5 -24.2 >24.15

% body

fat

Adjusted for age, sex &

current smoking

Primiparous

Multiparous

Mother’s body mass index in

early pregnancy (kg/m2 )

Parity p=0.004

Mother’s BMI in early pregnancy p<0.001

Reynolds & Godfrey et al (2010)

Diabetes free survival in offspring in relation to maternal age at delivery (UK).

Bingley P J et al. BMJ 2000;321:420-424

© 2000 by British Medical Journal Publishing Group

Cardwell CR et al Caesarean Section offspring

Interventions

• Success may depend on epigenetic status

in individual

Differential epigenomic and transcriptomic

responses in subcutaneous adipose tissue

between low and high responders to caloric

restriction.

Bouchard L et al (2010) Am J ClinNutr; 91:309–20.

• Significant DNA methylation differences at 35 loci were found between the high and low responders before dieting, with 3 regions showing differential methylation after intervention.

• Some of these regions contained genes known to be involved in weight control and insulin secretion, whereas others were localized in known imprinted genomic regions.

• Differences in gene expression profiles were observed only after dieting, with 644 genes being differentially expressed between the 2 groups.

• These included genes likely to be involved in metabolic pathways related to angiogenesis and cerebellar long-term depression.

Interventions

• Animal models provide proof of principle for

efficacy of pharmacological (e.g. statin),

endocrine (leptin) and nutritional (folate,

methyl donors) interventions

Interventions

• Animal models provide proof of principle for

efficacy of pharmacological (e.g. statin),

endocrine (leptin) and nutritional (folate,

methyl donors) interventions

• Encouraging evidence is emerging in

human, but effective interventions will

involve wider social support

Tobias DK et al (2012) Pre-pregnancy adherence to dietary patterns and

lower risk of gestational diabetes mellitus Am J Clin Nut: 96 289-95

Paternally Induced Transgenerational

Environmental Reprogramming of

Metabolic Gene Expression in Mammals

Carone BR et al (2010) Cell 143, 1084–1096.

Offspring of males fed a low-protein diet exhibited

elevated hepatic expression of many genes involved in

lipid and cholesterol biosynthesis and decreased levels

of cholesterol esters, relative to the offspring of males

fed a control diet. Epigenomic profiling of offspring

livers revealed numerous modest (20%) changes

in cytosine methylation depending on paternal diet,

including reproducible changes in methylation over

a likely enhancer for the key lipid regulator PPARa.

New Insights - Summary

• We need a new medical model for NCDs

• There is a very strong case for interventions in early life for NCD prevention

• We have biomarkers of later NCD risk which can be measured in early life

• We have moved from focusing on low birthweight to realise that effects on NCD risk are graded across the entire normal range of development

• NCDs do not start in development, but development influences responses to later challenges and so risk

• Pre-conception period may be critical in terms of health literacy and behaviour or parents-to-be

• Needs a focus on adolescent girls (and boys too)

• Promoting a healthy start to life means that we could show a beneficial effect of interventions within a short (<5 years) timeframe.

United Nations (Sept 2011): Political declaration of the High-level Meeting of the General Assembly on the Prevention & Control of Non-communicable Diseases

14. In 2008, an estimate 36 million of the 57 million global deaths were due to NCDs, .... and that nearly 80% of those deaths occurred in developing countries

26. {We} note also with concern that maternal and child health is inextricably linked with NCDs and their risk factors, specifically as prenatal malnutrition and low birth weight create a predisposition to obesity, high blood pressure, heart disease and diabetes later in life; and that pregnancy conditions, such as maternal obesity and gestational diabetes, are associated with similar risks in both the mother and her offspring

37. Acknowledge the contribution and important role played by all relevant stakeholders, including individuals, families, and communities, intergovernmental organizations and religious institutions, civil society, academia, media, voluntary associations, and where and as appropriate, the private sector and industry, in support of national efforts for NCD prevention and control

Welcome to DOHaD 2013

8th World Congress

17-20 November 2013

SINGAPORE