1. Biological Embedding: Implications for Neurodevelopment Clyde Hertzman, MD Human Early Learning Partnership University of British Columbia, Vancouver

2. Gradient in all Cause Mortality: UK Whitehall Study

3. CHD Mortality - UK Whitehall Study

4. 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’

5. Percent vulnerable and SES Canada Canada

6. Mexico Kosovo Australia Canada

7. Life Course Problems Related to Early Life 2 nd Decade 3 rd /4 th Decade 5 th /6 th Decade Old Age School Failure Teen Pregnancy Criminality Obesity Elevated Blood Pressure Depression Coronary Heart Disease Diabetes Premature Aging Memory Loss

8. 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

9. Archeology of Biological Embedding Gene Function Cell/Synapse Neural Circuitry Experience/Behavior

10. Surficial Archeology Gene Function Cell/Synapse Neural Circuitry Experience/Behavior (early development in context)

11. Sensitive Periods in Early Brain Development Vision 0 1237654 High Low Years Habitual ways of responding Emotional control Symbol Peer social skills Numbers Hearing Graph developed by Council for Early Child Development (ref: Nash, 1997; Early Years Study, 1999; Shonkoff, 2000.) Pre-school yearsSchool years Language

14. The Early Development Instrument

15. What Does the EDI Measure?

16. All Children Included in Age 5 School Entry Year

21. ‘Shallow’ Archeology Gene Function Cell/Synapse Neural Circuitry Experience/Behavior

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

23. SES Differences in Prefrontal Cortex Activity by School Age

24. Deep Archeology ‘Social Epigenesis’ and other processes that can influence gene expression

25. mRNA Translation protein Coding sequence StopStart Promoter RNA plmrs RNA plmrs TFTF TFTF Transcription Molecular level CH 3

26. 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?

27. Biological Embedding: Epigenetic Marks of Early Life Early Life 15-40 yrs

28. 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

29. 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!

30. Wisconsin Study of Families and Work Essex, Boyce, Hertzman & Kobor, 2011 N = 570 Stress: depression symptoms expressed anger parenting stress role overload financial stress Preschool Infancy N = 109 Epigenetic profiling: Buccal epithelial cells Illumina microarray ~28,000 CpG sites in ~14,000 gene promoters

31. 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

32. 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)

33. 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)

34. 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

35. 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

36. 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

37. 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.)

38. www.earlylearning.ubc.caMerci!