Biological Embedding: Implications for

Neurodevelopment Clyde Hertzman, MD

Human Early Learning PartnershipUniversity of British Columbia, Vancouver

Gradient in all Cause Mortality: UK Whitehall Study

CHD Mortality - UK Whitehall Study

SEP Gradients in Health: Social Determinants to Early Development• ubiquitous in wealthy and majority world countries

by income, education, or occupation• cuts across a wide range of disease processes• not explained by traditional risk factors• replicates itself on new conditions as they emerge• occurs among males and females• begins life as gradient in ‘developmental health’

with life course persistence and ‘flattening up’

very poor poor not poor well-off0

10

20

30

40

50

60

31.9 29.123.1

13.7

% vulnerable

Percent vulnerable and SESCanada

very poor poor not poor well-off0

10

20

30

40

50

60

31.929.1

23.1

13.7

% vulnerable

Canada

Q1 Q2 Q3 Q40

10

20

30

40

50

60

56.3

43.240

30.8

% vulnerable

Very poor Poor Not poor Rich0

10

20

30

40

50

60

27.323.9

17.5 16.1

% vulnerable

Mexico

Kosovo

Australia

Canada

Bottom 10%

10-25% 25-50% 50-75% 75-90% Top 90%0

10

20

30

40

50

60

35.3

27.6 26.324

18.7

11.2

% vulnerable

Percent vulnerable and SES

Life Course Problems Related to Early Life

2nd Decad

e

3rd/4th Decad

e

5th/6th

Decade

Old Age

• School Failure

• Teen Pregnancy

• Criminality

• Obesity

• Elevated Blood Pressure

• Depression

• Coronary Heart Disease

• Diabetes

• Premature Aging

• Memory Loss

Biological embedding occurs when • experience gets under the skin and alters human

biodevelopment;• systematic differences in experience in different

social environments lead to different biodevelopmental states;

• the differences are stable and long-term;they influence health, well-being, learning, and/or behaviour over the life course.

Biological Embedding

Archeology of Biological Embedding

Gene Function

Cell/Synapse

Neural Circuitry

Experience/Behavior

Surficial Archeology

Gene Function

Cell/Synapse

Neural Circuitry

Experience/Behavior(early development in context)

Sensitive Periods in Early Brain Development

Vision

0 1 2 3 7654

High

LowYears

Habitual ways of respondingEmotional

control

Symbol

Peer social skillsNumbers

Hearing

Graph developed by Council for Early Child Development (ref: Nash, 1997; Early Years Study, 1999; Shonkoff, 2000.)

Pre-school years School years

Language

The Early Development Instrument

What Does the EDI Measure?

All ChildrenIncluded in Age 5 School Entry Year

‘Shallow’ Archeology

Gene Function

Cell/Synapse

Neural Circuitry

Experience/Behavior

Shallow Archeology

• HPA axis --- cortisol• ANS system --- epinephrine/ne• Prefrontal cortex• Social affiliation --- amygdala/locus cereleus• Immune function -- the ‘peripheral brain’

SES Differences in Prefrontal Cortex Activity by School Age

Deep Archeology

‘Social Epigenesis’ and other processes that can influence

gene expression

mRNATranslation

protein

Coding sequence StopStart

PromoterRNA

plmrs

Transcription

Molecular level

CH3

It does not only occur during basic fetal development, when cells are specializing……it can continue after birth and be influenced by the broader environment!

What’s new about this?

Biological Embedding: Epigenetic Marks of Early Life

Early Life 15-40 yrs

1958 British Birth Cohort Study

(Int J Epid, March 2012)

• 40 adult males selected from SES extremes in both childhood and adulthood

• Genome-wide methylation analysis from blood DNA at 45 years of age

• 20,000 gene promoter regions

Methylation levels for 1,252 promoters associated with childhood SEP

Methylation levels for 1,141 promoters associated with childhood abuse

But only approx. 80 promoters associated with maternal smoking during pregnancy!

Wisconsin Study of Families and Work

Essex, Boyce, Hertzman & Kobor, 2011

N = 570

Stress:•depression symptoms•expressed anger•parenting stress•role overload•financial stress

PreschoolInfancy

N = 109

Epigenetic profiling:•Buccal epithelial cells•Illumina microarray•~28,000 CpG sites in ~14,000 gene promoters

• Differential methylation of multiple CpG sites by parental stress in infancy and preschool

• Mothers’ stressors in infancy more related to differences in methylation for both girls and boys

• Fathers’ stressors in preschool associated with methylation differences primarily for girls

• A pattern commensurate with prior knowledge of maternal v paternal and gender-specific influences on development

Epigenetic vestiges of early developmental adversity

Since 2010, 34 life course studies have included measurements of DNA

methylation

Ng et al. Genome Biology 2012,

(Ng et al, Genoome Biology 2012; 13:246)

Journal Articles Referring to Biological Embedding*

* Databases searched by M. Wiens -- Ebsco, Google Scholar, PubMed, Scirus, and Web of Knowledge -- August 2012**2012 includes Jan-July only (part-year)

Milestones in Biological Embedding 1

• 2004: Meaney/Szyf paradigm first cited as animal evidence of biological embedding

• 2006: first human GxE interaction (childhood maltreatment by MAOA) to be cited as evidence of biological embedding

• 2006: biological embedding first used to account for development origins of adult disease

• 2006: biological embedding linked to racial health disparities in North America

Milestones in Biological Embedding 2

• 2008: biological embedding first used to account for why parents’ social standing is associated with neural development in brains of children

• 2008: biological embedding first used to account for the childhood SES/CHD risk relationship

• 2008: biological embedding first used to justify investment in the early years as human capital investment

• 2010: biological embedding first used to ‘explain’ life course influences of ACE’s

Milestones in Biological Embedding 3• 2010: biological embedding first used as central

organizing concept in ‘stress’ study (of inflammation)

• 2011: biological embedding first demonstrated in human epigenetics

• 2011: biological embedding used to account for SES differences in telomere length

• 2012: biological embedding first used to account for validity of allostatic load

2011: Biological Embedding becomes Conventional Wisdom

“A scientific consensus is emerging that the origins of adult disease are often found among developmental and biological disruptions occurring during the early years of life. These early experiences can affect adult health in two ways – either by cumulative damage over time or by the biological embedding of adversities during sensitive developmental periods……..”

(Leckman JF, March JS. Editorial: Developmental neuroscience comes of age. J Child Psychol Psychiatr. 2011;52(4):333-8.)

www.earlylearning.ubc.caMerci!