Developmental programming environment before you were born … · 2012. 3. 1. · environmental...

Developmental programmingDevelopmental programming or how your parentsor how your parents’’ environment environment

before you were born impacts on your and your before you were born impacts on your and your childrenschildrens’’ risk of diseaserisk of disease

Jonathan Seckl

Scottish CuisineScottish Cuisine and diseaseand disease

"Without stress, there would be no life" Hans Selye

GlucocorticoidsGlucocorticoids•

Mobilise fuel–

Glucose

– Fatty acids

– Proteins

• Increase blood pressure

• Euphoria

• Inhibit–

inflammation

– immune responses

– wound healing

– digestion

– growth/bone formation

– reproduction

– detailed learning and memory

cortisol

2

O

C = O

CH OH

O HH O

Cortisol

....

Cushing’s Disease

• High blood pressure• diabetes• high blood cholesterol• abdominal obesity• stretch marks• bruising• osteoporosis• muscle weakness• infertility• depression• memory loss

XX

Nature and nurtureNature and nurture

But

Identical twins reared apart from birth (same genes, different environment)……

have the same concordance of many diseases (schizophrenia, diabetes, etc) as those reared together (same genes, same environment).

This suggests that the environmental factors that underlie the differences between identical twins operate BEFORE or at birth.

Birth weight and adult diseaseBirth weight and adult disease

8.5 lbs (~4 kg)8.5 lbs (~4 kg) 5.5 lbs (~2.4 kg)5.5 lbs (~2.4 kg)

Ethel Margaret BurnsideEthel Margaret Burnside HertfordshireHertfordshire’’s s ‘‘Lady Inspector of MidwivesLady Inspector of Midwives’’ (1911(1911--30)30)


Barker et al, 1990, BMJ, 301:259

Low birth weight and risk of T2D/MSLow birth weight and risk of T2D/MS

Hales et al, BMJ 1991; Barker et al, Diabetologia 1993; Whincup et al, JAMA 2008

Systematic review Systematic review

• 30 reports, 152000 subjects

• Pooled OR 0.75/kg (CI 0.70-0.81)

• Not reduced by adjusting:

– adult BMI

– SE status

Type 2 diabetes Metabolic syndrome

10

5

20

10

<5.5 -6.5 -7.5 -8.5 -9.5 >9.5

Odd

s ra

tio

<5.5 -6.5 -7.5 -8.5 -9.5 >9.5Birth weight (lbs) Birth weight (lbs)

from the Hertfordshire cohort study: Thompson et al BJPsych 2001

Birth weight and depression aged 68 yearsBirth weight and depression aged 68 years

Odds ratio

P=0.02

0

0.5

1

1.5

2

2.5

3

3.5

<6.5 6.5-7.5 7.5-8.5 >8.5

<5.5<5.5 --6.56.5 --7.57.5 --8.58.5 --9.59.5 >9.5>9.5

400400

200200

300300

plasmaplasmacortisolcortisolnmol/lnmol/l

Birth weight (lbs)Birth weight (lbs)

P=0.001P=0.001n=423n=423

Plasma Plasma cortisolcortisol in 64y old men correlates negatively in 64y old men correlates negatively

with birth weightwith birth weight

Phillips et al, Phillips et al, JCE&MJCE&M, 1998, 1998


8.7 lbs4 kg

5.3 lbs2.4 kg

low birth weight

• hypertension• type 2 diabetes• hyperlipidaemia• metabolic syndome• coronary heart disease• osteoporosis• depression, anxiety, psychosis

• Increased overall mortality

• Butterflies hatched during different seasons were coloured differently

• Season-dependent colouration mimicked by larval incubation temperature

summer winter

Weissman 1893

The environment and regulation of The environment and regulation of development development

• The phenomenon is widespread (ubiquitous)

• It is adaptive– In a famine-striken warzone the ‘small baby’ phenotype

appears beneficial (low birth weight, rapid growth, higher BP, waryness, early puberty, etc)

• A tiny improvement in individual survival over evolutionary time would maintain the processes

• Associations with disease reflect contemporary concerns and miss the underlying biology

• We do not (yet) understand most of the ‘rules’– low b. wt is a blunt marker of ‘something challenging happened’

Developmental programming is Developmental programming is notnot about about diseasedisease

Mechanisms linking to adult diseaseMechanisms linking to adult disease

Possible mechanisms• genetics

8.7 lbs (4 kg) 5.3 lbs (2.4 kg)


8.7 lbs (4 kg) 5.3 lbs (2.4 kg)

Possible mechanisms• genetics• Socio-economic class

Mechanisms linking to adult diseaseMechanisms linking to adult diseasePossible mechanisms• genetics• socio-economic class• maternal malnutrition

8.7 lbs (4 kg) 5.3 lbs (2.4 kg)

PrePre--natal starvationnatal starvation……Dutch Hunger Winter 1945 and Chinese Famine 1959Dutch Hunger Winter 1945 and Chinese Famine 1959--6161

offspring show:-• small reduction in birth weight• increased schizophrenia• addiction and depression• increased diabetes• increased blood pressure• more heart disease• higher cortisol

levels

‘We Were So Hungry We Ate Tulips’

Father Leo Zonneveld


Possible mechanisms• genetics• social class• maternal malnutrition

2

O

C = O

CH OH

O

8.7 lbs (4 kg) 5.3 lbs (2.4 kg)

• glucocorticoids• reduce birth weight

• alter organ maturation• cause hypertension,

diabetes, depression, etc• Sex steroids ‘programme’

Prenatal glucocorticoid excess ‘programmes’ higher BP and glucose in adult offspring

systolic BP

120

130

140

150

160*

*

female male

controldexamethasone

mmHg

insglu

no inject saline dexwk 1

dexwk 2

dexwk 3

0

1

2

3 *

Single dose of Single dose of betamethasonebetamethasone ‘‘programmesprogrammes’’ insulin insulin resistance 30 years later: resistance 30 years later: Lancet 28Lancet 28thth May 2005May 2005

11-HSD-2

VOL 341: FEB 6, 1993 355

Dysfunction of placental glucocorticoid

barrier: link between fetal

environment and adult hypertension?

CHRISTOPHER R. W. EDWARDS RAFN BENEDIKTSSON ROBERT S. LINDSAY

JONATHAN R. SECKLBirthweight is associated with the subsequent development of common

disorders of adult life, especially hypertensior;:' maternal malnutrition has been suggested as the cause. We suggest an alternative aetiology- increased fetal exposure to maternal glucocorticoids. This hypothesis is supported by our findings that in rats decreased activity of the enzyme that acts as a placental barrier to maternal glucocorticoids (11~-hydroxysteroid dehydrogenase) is associated with low birthweight Furthermore, increased exposure of the fetus to exogenous glucocorticoids leads to low birthweight and subsequent hypertension in the offspring. Glucocorticoids acting during critical periods of prenatal development may, like other steroid hormones, exert organisational effects or imprint patterns of response that persist throughout life. Thus, the lifetime risk of common disorders may be partly determined by the intrauterine environmentLancet 1993; 341: 355-57.

whereas weight at 12 months correlates closely with weight subsequently. to This fInding suggests that in both animals and man there are local maternal factors, quite distinct from the maternal and paternal genes affecting the infant's ultimate size, which limit the growth of the fetus. Physical limitation of uterine space is not an important factor in rabbits,9 although the evidence in man is less clear.5 Whatever these maternal factors are, there could be catch-up growth after birth. It is interesting that adolescents with the highest blood pressures are those who grow fastest as children.ll

There are clear geographical differences in the incidence of cardiovascular disease in the UK; the correlation between these variations and blood pressure,12 suggests that there are important environmental determinants of blood pressure. Maternal smoking can affect fetal growth, but not placental weight.14 Moreover, smoking is associated with proportional reductions in birthweight and length, 15for any birthweight, head circumference increased with placental weight, but body length decreased. The Preston investigators5 suggested that there might be diversion of blood away from the trunk

Placental 11Placental 11--HSD2 activityHSD2 activity

ratrat humanhumanDeficiency of the placental cortisol barrier and reduced birth weight

placental 11β-HSD2

*

362 US babies

Huh et al, BMC Med 2008Quartile of E/(E+F) ratio

*

80

84

88

92

96

100

50

54

58

62Diastolic BPmmHg

Systolic BPmmHg

Placental 11Placental 11ββ--HSD2 predicts BP at 3yrsHSD2 predicts BP at 3yrs

1111ßß--HSD inhibition programmes increased HSD inhibition programmes increased blood pressure and glucoseblood pressure and glucose

112200

113300

114400

115500 *

00

11

22

33

44

55

66

55

66

77

88

99

controlCBX

12012090906060303000 minmin

**

* **

control CBX control CBX

birth weightbirth weight blood pressureblood pressure blood glucoseblood glucose6 months

Lindsay et al, Lindsay et al, HypertensionHypertension, 1996, 1996Lindsay et al, Lindsay et al, DiabetologiaDiabetologia, 1996, 1996

Pla

cen

tal

11

β-H

SD

2

•• cortcort•• other placentalother placental

and maternal and maternal factorsfactors

dietdiet stressstress diseasedisease

PlacentalGC barrier

0

5

10

15

20

25

30

35

22% 18% 9%

Placental 11Placental 11ββ--HSD2 deficiency: key to developmental HSD2 deficiency: key to developmental programming?programming?

Langley-Evans et al, 1996

Protein restriction

**

*

**

Mairesse et al, 2007

stress

con stress

Maternal anxiety, reduced placental 11β-HSD2 and increased fetal cortisol

Glover, O’Donnell et al, Psychoneuroendocrinol, 2009; 2011

Pla

cen

tal 1

1β-

HS

D2

Pla

cen

tal 1

1β-

HS

D2

Maternal anxiety scoreMaternal anxiety score

Feta

lco

rtis

ol

Maternal cortisol

A Finnish favouriteA Finnish favourite

Glycyrrhiza glabra

Maternal licorice consumption reduces offspring cognition and increases ADHD

0.0153.2 (8.7)49.1 (9.1)Total behavior problems

0.0353.6 (8.8)50.1 (8.4)Externalizing symptoms

0.1352.7 (9.5)50.4 (9.9)Internalizing symptoms

Child Behavior Checklist

0.049.3 (3.4)10.4 (3.1)Narrative memoryDevelopmental Neuropsychological Assessment

0.2399 (14.9)102 (12.3)Beery Development Visual-Motor Integration

0.4610.3 (3.6)10.8 (3.1)Symbol search

0.049.8 (3.1)10.9 (2.9)Block design

0.0110.2 (3.3)11.6 (3.1)Similarities

0.0210.4 (2.8)11.6 (3.0)Vocabulary

Wechsler Intelligence Scale for Children III

M (SD)M (SD)

N = 62N = 202

High

> 500 mg/week

Zero-low

0-249

P value

Maternal consumption of glycyrrhizin

Räikkönen et al, Am J Epid 2010

Effects persist after adjusting for……child’s sex, age, length of gestation, birth weight, head circumference, birth order, mother’s age, occupational status, smoking, alcohol consumption, psychological stress during pregnancy,

mode of delivery, gestational diabetes, gestational hypertension and preeclampsia

0.0425.9 %15.4 %Attention Deficit Hyperactivity Disorder

How to programme a tissue?How to programme a tissue?

• alter cell number– proliferation– apoptosis

• alter gene expression– chromatin

• histones (acetylation, methylation)• DNA methylation

– transcription factors

1Z 21Bmmmmmm

Prenatal challenges programme the Prenatal challenges programme the glucocorticoidglucocorticoid receptor, but in a cellreceptor, but in a cell--specific mannerspecific manner

Nyirenda et al, JCI, 1998; Cleasby et al, Endo, 2003

**

visceral

1.0

0.5

subcutperivenous periportal0

100

200

300

400 **

adiposeliver

DG CA1 CA2 CA3

hippocampus

* *

Levitt et al, Neuroendocrinol, 1996

11 14 1111715 16 2

17 2-9

16 2-9

19 2-9

liver hippoc thymus

+++ +++ +++

- ++ -

++ - -

- - ++

AP2 NGFIA

n >11

11018

11 2-9

19

McCormick et al, Mol Endo, 2000

>30kb

The GR gene contains multiple alternate, tissueThe GR gene contains multiple alternate, tissue--specific specific 1st 1st exonsexons

5HT

PKAcAMPCa++

GR geneGR gene11 14 1111715 16 211018 19

AP2 NGFIAP2 NGFI--AA

17 2-9

17 2-9

17 2-9

prenatal GCexcess

5HT regulates hippocampal

GR gene transcription

How can early life events affect someone for the rest

of their lifespan?

epigeneticsepigenetics

epigenetics

EpigeneticsEpigenetics -- the differences in geneticallythe differences in genetically--identical identical individuals grown in different wombs individuals grown in different wombs

CopycatCopycat CopycatCopycat’’s s ‘‘mummum’’

Weaver et al, Nature Neurosci 2004

CpG

C-m

eth

yla

tio

n(%

)

Early life environment determines the epigenetic state Early life environment determines the epigenetic state ((methylationmethylation) of the GR 1) of the GR 1 77 promoterpromoter

16 17

17

NGFI-A

5’ CpG 3’ CpG 100

80

60

40

20

0

**

E20 P1 P6 P21 P90 E20 P1 P6 P21 P90C-m

eth

yla

tio

n(%

)

100

80

60

40

20

0

* *

Age (dy)

Lower total DNA methylation with low SES

McGuinness et al, Int J Epidemiol 2012

no

n-m

an

ual

man

ual

3535--44 y44 y 4545--54 y54 y 5555--64 y64 y

no

n-m

an

ual

man

ual

no

n-m

an

ual

man

ual

no

n-m

an

ual

man

ual

man

ual

no

n-m

an

ual

man

ual

no

n-m

an

ual

man

ual

no

n-m

an

ual

man

ual

man

ual

no

n-m

an

ual

man

ual

no

n-m

an

ual

man

ual

no

n-m

an

ual

man

ual

no

n-m

an

ual

man

ual

no

n-m

an

ual

man

ual

3535--44 y44 y 4545--54 y54 y 5555--64 y64 y3535--44 y44 y 4545--54 y54 y

The excitement of steroid metabolism

Children exposed to the Holocaust

Lower Lower glucocorticoidglucocorticoid metabolism in Holocaust survivorsmetabolism in Holocaust survivors

0.99 ±

0.08**1.23 ±

0.0811ß-HSD2 ratio

7.4 ±

1.48.0 ±

1.55-red ratio

5.6 ±

0.7**17 ±

45-red ratio

1600 ±

3001900 ±

4005-THF

2500 ±

400**5600 ±

6005-THF

6500 ±

600*11000 ±

1200Total glucocorticoids

Controls (n=22) Holocaust survivors (n=51)

Yehuda et al, J Psychiatr Res 2009

Younger at trauma - greater decrease in metabolism

Steroid metabolism

Age at trauma ‘exposure’5 10 15 20 years

‘normal’ range

0

9.11 study9.11 study -- 1 yr old offspring 1 yr old offspring cortisolcortisol

altered: altered:

only after 3only after 3rdrd trimester exposuretrimester exposure

First Trimester

0

1

2

3

4

5

6

7

8

Log

Saliv

ary

Cor

tisol

(nm

/uL)

Second Trimester

012345678

Third Trimester

012345678

am pm am pm am pm

YehudaYehuda et al, et al, JCE&MJCE&M, 2005, 2005

cortisol cortisone

5-dihydrocortisol

5-reductase

11β-HSD2

INTRACRINE EFFECTSINTRACRINE EFFECTS2 enzymes are reduced permanently in youngest exposed to Holocau2 enzymes are reduced permanently in youngest exposed to Holocaustst

Both seem plausible early life adaptations to starvation/stress

Increased fuelGlucoseCholesterol and fats

Increased BPSalt retentionBlood pressure

Programmed for deprivation… (famine, physical challenge)….

then born to EXCESS and STRESS

Obesity Trends* Among U.S. Adults BRFSS, 1985


>30%

Source: Behavioral Risk Factor Surveillance System, CDC.


(*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

PTSD after Holocaust PTSD after Holocaust traumatisationtraumatisation associates associates with with ‘‘metabolic syndromemetabolic syndrome’’

020406080

100120140160180200

Controls Holocaust survivorsPTSD+

Perc

ent w

ith sy

mpt

omBMI>25Atherosclerosis and/or HyperlipidemiaDiabetesHypertension

‘‘IntergenerationalIntergenerational’’ effectseffects

Birth weightBirth weight Glucose homeostasisGlucose homeostasis

Intergenerational effects of prenatal stressIntergenerational effects of prenatal stress

F1F100

1010

2020

**

00

11

22

33

44

55

66

gg

F1F1 F2F2

**

*

F2F2

**

Drake et al, Am J Drake et al, Am J PhysiolPhysiol 20052005

EpigeneticsEpigenetics??

*†

02468

1012141618

F2 veh F2 dex F2 veh/dex F2 dex/veh

*

*†*†

02468

1012141618


*

*†*†

02468

1012141618


*

*†

Liver glucose production

veh vehdex dexMother as fetusFather as fetus

Drake et al, Am J Drake et al, Am J PhysiolPhysiol 20052005

Fetal liver F1

F2

Veh/VehDex/DexDex/Veh MATERNALVeh/Dex PATERNAL

0.5

1

1.5

2

Igf2 Cdkn1c GR

mR

NA

**

**

0

0.5

1

1.5

2

2.5

Igf2 cdkn1c(Grb10)

GR

*

*

Phlda2

Phlda2

* *

The changes differ in the first and second generationsThe changes differ in the first and second generations

Drake et al, Epigenetics, 2011

*

Epigenetic effects also differ in the first and second Epigenetic effects also differ in the first and second

generationsgenerations

% m

ethy

latio

n

0

10

20

30

40

50

60

DMR2

saldex

**

Drake et al, Epigenetics 2011

0

30

40

50

60

ICR

*

F1=DMR2 F2=ICR

*

P0 P1 P2 P3

H19DMR1DMR0 DMR2 ICR

PaternalMaternal

15-30% methylation

difference in Beckwith-Weidermann

and Silver-Russell syndromes

Overkalix

You are what your grandparents ate?You are what your grandparents ate?

Pembrey et al, Eur J Hum Gen, 2006

Gra

nd

son

’s m

ort

ali

tyR

ela

tive r

isk

Gra

nd

dau

gh

ter’

s m

ort

ali

tyR

ela

tive r

isk

2.0

1.0

0.5

2.0

1.0

0.5

GrandparentGrandparent’’ssNutrition in Nutrition in childhoodchildhood

PoorPoorGoodGood

0 2 4 6 8 10 12 14 16 18 20Paternal Grandmother’s age

0 2 4 6 8 10 12 14 16 18 20Paternal Grandfather’s age

And unto the next generation?And unto the next generation?

This suggests that parental PTSD is a ‘vulnerability factor’ for offspring PTSD

•• 50% Holocaust survivors have PTSD 50% Holocaust survivors have PTSD (5(5--10% normal population)10% normal population)

•• 30% of survivors30% of survivors’’ children have PTSDchildren have PTSD

•• These children do not appear to have These children do not appear to have experienced more major traumaexperienced more major trauma

•• Holocaust exposure predicts offspring Holocaust exposure predicts offspring depression, ..but survivor PTSD depression, ..but survivor PTSD predicts offspring PTSDpredicts offspring PTSD

PlasmaCortisol(ug/dl)14

6

4

06 12 18 24 h

ControlsNo parental PTSDPaternal PTSDMaternal PTSD

You are shaped by your motherYou are shaped by your mother’’s stress:s stress:maternal PTSD & her healthy offspringmaternal PTSD & her healthy offspring’’s s cortisolcortisol

12

10

8 **

Yehuda et al, Arch Gen Psych 2008

Maternal PTSD also impacts steroid enzymes in her Maternal PTSD also impacts steroid enzymes in her childrenchildren

No ParentExposed

No ParentsPTSD

Father PTSD

MotherPTSD

Both Parents PTSD

0

0.2

0.4

0.6

0.8

1

Rat

io E

/F

11β-HSD2

0

1000

2000

3000

4000

5000

6000

No Parentalexposure

No ParentsPTSD

Father PTSD

MotherPTSD

Both ParentsPTSD

5-reductase

Yehuda et al, unpublished

9.11 study9.11 study lower 5lower 5--reductase reductase predictspredicts PTSDPTSD

Yehuda et al, Yehuda et al, PsychoneuroendocrinologyPsychoneuroendocrinology 20092009

0

1

2

3

4

5

11-HSD 11-HSD2

Non-recoverers

Recoverers

0

0.04

0.08

0.12

5

reductase 5

reductase

11β-HSDs A ring reductases

*

So what can be done?So what can be done?

The 1960s MotherwellThe 1960s Motherwell dietdietIMPORTANT. This is a special diet for expectant mothers. If you

ADD to it or TAKE from it, it is no longer special

1. Meat – One pound of red meat should be eaten every day of gestation. Quantity is more important than quality.

2. Green vegetables – try to eat twice daily. Do not eat peas, beans, turnip, parsnip, carrot or beetroot

3. Sweets – should be limited to ½ pound of boiled sweets per week. Do not eat chocolate

4. Do not eat potatoes or chips, breads, rolls, scones, cakes or biscuits of any kind

5. Do not eat milk puddings, cereals, macaroni, spaghetti and ice cream

If you persevere with this diet for three weeks it becomes natural and easy…………

The advantages of success in controlling your diet……come only if you are successful, not just trying

HF inHF in pregnancy:pregnancy:

increased cortisol in 30y offspringincreased cortisol in 30y offspring

Maternal meat & fish intake(portions /week)

trend p<0.05

350

400

450

500

550

Plasma cortisol(nmol/l)

<11 12 -15 16 -

21 >21

Reynolds et al, JCEM 2007

Biomarkers and stratified therapy?Biomarkers and stratified therapy?

Reynolds, Drake et al, unpublished

0 2 4 6 8 10 12 14 16 18 20 22 24

Meat portions in late pregnancy

-1

0

1

2

3

4

5

6

Glu

coco

rtico

id re

cept

or m

ethy

latio

n (%

)

r=0.53, p=0.003

Adult GR 1Adult GR 177

and maternal dietand maternal diet

Meat portions in late pregnancy

0 4 8 12 16 20

GR

17

mR

NA

(%

)

Metformin reversesMetformin reversesincreased liver GRincreased liver GR

*

control

GR

mR

NA

Cleasby et al, Endo, 2003

metformin

Give methyl donors (Give methyl donors (folate, choline, Vit B12, betainefolate, choline, Vit B12, betaine))

Leptin reverses low protein effects on placental Leptin reverses low protein effects on placental 1111ββ--HSD2 and birth wtHSD2 and birth wt

0

5

10

15

20

25

**

% C

onve

rsio

n B

to A

Placental 11β-HSD2 activity

Saline Saline Saline Saline LeptinLeptinChow Chow LP LP LPLP

0.0

1.0

2.0

3.0

4.0

5.0

Feta

l wt (

g)

**

Saline Saline Saline Saline LeptinLeptinChow Chow LP LP LPLP

Fetal wt

Stocker et al, Int J Ob, 2004

SummarySummary

• A variety of environmental factors ‘programme’ the offspring for the lifespan

• The outcomes of different maternal challenges are rather similar

• Maternal stress and its glucocorticoid hormone mediators is a powerful programming influence

• Placental 11β-HSD2 affords one link between maternal, placental and fetal environments

• Epigenetic alterations are likely to underpin some of these effects

• The brain is particularly vulnerable to fetal programming

• Programmed changes in glucocorticoid metabolism may impact vulnerability to mood disorders, notably PTSD

• Effects persist into a second generation

• Not everything is written in your genes and epigenes

And the Future?And the Future?

• We don’t yet know how important these early life impacts are, nevertheless..

• Epigenetic marks may measure individual exposure and risk

• They are relatively stable, unlike many blood tests and other measures in adult life

• Epigenetic changes are also potentially modifiable, unlike genetics

• If we can understand the ‘rules’ we may be able to target screening and ‘prevention’ to those at greatest risk

• We may also find ways to personalise therapy depending on the individual ‘cause’ of disease

• However, this biology has survived hundreds of millions of years of evolution because, on balance, it is beneficial to the individual, so interfering blindly may give unwanted consequences

Edinburgh

Amanda DrakeLizzy Cottrell

Caitlin WyrwollRafn Benediktsson

Robbie LindsayRoger Brown

Moffat NyirendaMark CleasbyLincoln Liu

Chris KenyonLeonie Welberg

Justin TangAnnick deVriesMegan HolmesKaren ChapmanJim McCormick

Dawn LivingstoneRebecca Reynolds

Ruth AndrewRichard Meehan

11ß-HSD KOsJohn Mullins

Janice PatersonYuri Kotelevtsev

Collaborations

Mt Sinai, New YorkRachael Yehuda

Linda Bierer

SouthamptonDavid BarkerDavid PhillipsKeith Godfrey

Simon Langley-EvansMark Hanson

BuckinghamClaire Stocker

Mike Cawthorne

McGillMichael Meaney

Josie DiorioIan WeaverMoshe Szyf

Collaborations

HelsinkiKatri RaikkonenJohan Eriksson

DallasDavid Russell

Mala Mahendroo

We canWe can’’t avoid early life stresst avoid early life stress

Strewth Bruce! Is that you?

Methyl donor (icv) methylates GR1Methyl donor (icv) methylates GR177

in adult hippocampus in adult hippocampus

Developmental programming environment before you were born … · 2012. 3. 1. · environmental...

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