5 SEPTEMBER 2012

New cohorts to examine interactions among childhood social adversity and

environmental factors on disease development and prevention

Panayiotis Yiallouros M.D, Ph.D.1,2

1DEPT OF PAEDIATRICS, ARCH. MAKARIOS III HOSPITAL,

MINISTRY OF HEALTH, CYPRUS

2CYPRUS INTERNATIONAL INSTITUTE FOR

ENVIRONMENTAL AND PUBLIC HEALTH IN

ASSOCIATION WITH HARVARD SCHOOL OF PUBLIC

HEALTH – CYPRUS UNIVERSITY OF TECHNOLOGY

Changes in the Prevalence of Diagnosed Asthma and Asthma Symptoms over Time in Children and Young Adults

Eder W et al. N Engl J Med 2006;355:2226-2235

‘‘Conclusion: The prevalence of allergic

diseases in Cyprus is still on the rise;

recent increases appear more

pronounced among children living in

rural areas possibly indicating recent

environmental and lifestyle changes in

these communities’’

Lifelong impact of early life respiratory morbidity

Established Risk Factors for Adult Asthma

Bad choice of parents–Genetics

Childhood history of breathing problems

Occupation Smoking Viral upper respiratory tract infections Air pollution indoor / outdoor

Stern DA, et al. The Lancet 2008; 372:1058-1064

‘‘Conclusion: .. Increased

risk of hospitalization at

elevated levels of

particulate matter and

ozone consistent with the

magnitude seen across

several European cities ….

….Increased risk for

hospitalization on dust

storm days, particularly for

cardiovascular causes’’

Living near a power plant and the risk of wheezing in adolescents in Cyprus

(Middleton et al, submitted in Eur J Public Health )

Active

Asthma

OR 95% CI

Within 5 km 1.67 1.14, 2.46

5-10 km 1.15 0.89, 1.50

10-15 km 1.41 0.45, 4.40

15-30 km 1.11 0.83, 1.47

> 30 km 1.00

P-value for trend <0.01

Odds ratios by distance of municipality of residence to the

nearest power station (restricted to rural areas & adjusted for co-morbidity)

n=6,393

Introduction – Observations(Bullard 1990; Graves 1988)

Environmental exposures (i.e.

traffic-related & industrial air

pollution)

Social stressors (i.e. noise, violence, poverty)

Spatial correlation &

cluster

Lower-income

communities Lower property

values

Highways, Industrial corridors, Power

Plants

Introduction Observations

Most pollution-exposed

communities

– higher prevalence of social

stressors (Lipfert 2004).

– may also be more

susceptible (through

alterations in immune

function and biological

systems)

Spatial clustering - Potential

for confounding

Effect modification by social

stressors

Social stressors may lead to

poor health outcomes

directly (McEwen and Seeman 1999).

Need to disentangle interaction of social and physical environmental risks

understand synergies among these exposures,

identify modifiable exposures

Inform Public Health Policy how best protect susceptible populations and improve overall population health

Outline of presentation

Effects of stress on respiratory health and susceptibility

Epidemiologic and toxicologic evidence of synergistic effects of stress and pollution

Pathways through which stress may influence pollution susceptibility

Provide a framework to examine combined effects on health across disciplines

– disentangle effects of spatially clustered social and environmental exposures

– explore potential synergies among these exposures.

Laura Kubzansky

Associate Professor of Society,

Human Development, and Health

Harvard School of Public Health

&

Harvard – Cyprus Program

Effects of stress on respiratory health and susceptibility

chronic stress has been linked to asthma symptoms in cross-sectional studies (Oh et al. 2004)

among asthmatic adolescents, SES has been associated with stress-linked immune mediators [IL-5, interferon-γ] (Chen 2003).

acute stressors (e.g., violent events) may trigger asthma episodes(Sandberg 2000, 2004)

older individuals with greater psychological distress and angerdisplay faster lung function decline over time (Kubzansky 2002).

prospective studies link caregiver stress to infant wheeze (Wright 2002).

Mothers’ anxiety during pregnancy is associated with asthma in their children

Asthma No asthma CRUDE

1st quartile (0-2) 198 1734 1 (reference)

2nd quartile (3-4) 174 1176 1.30 (1.04,1.61)

3rd quartile (5-7) 200 1295 1.35 (1.10,1.67)

4th quartile (8-16) 163 870 1.64 (1.31,2.05)

<0.001

Maternal anxiety at 18 weeks

P-value (trend)

OR = (163 / 870) / (198 / 1734) = 1.64

Percentage Increase = (1.64 -1) x 100 = 64% more likely to be

asthmatics at age 7.5 years when compared to children whose

mothers are in the 1st quartile

Cookson JACI 2009

Assessing stress chronicity is important ….

Acute stress is linked to…– sympathetic innervation,

including increased ventilation and bronchodilation

– plausibly masking some short-term effects air pollution effects (e.g., acute irritation, bronchoconstriction).

Chronic stress can produce…

– wear and tear on bodily systems, weaken immune function, and increase pollution susceptibility.

– relative chronicities of stress and pollution exposures is critical in accurately characterizing their interplay and in interpreting interactions.

Acute stress, sympathetic regulation and the short term response

Sympathetic nervous system activation under acute stress produces immediate, short-term response.

– Catecholamines (e.g., epinephrine and norepinephrine) produced from neural synapses produce

– Glucocorticoids are produced (including cortisol) increase heart rate, ventilation, myocardial contraction force, arterial

vasodilation to working muscles, and dilating pupils and bronchi.

– Parasympathetic nervous system–regulated activities subside

– Frequent sympathetic nervous system dominance under repeated acute stress may interfere with growth and repair,

– Important for developing children: one pathway through which childhood stress may shape lifelong health and susceptibility.

Chronic stress, immune function, and inflammatory response

Chronic stress may be characterized by recurrent acute stress or an inability to moderate acute stress responses (McEwen 1999).

Endocrine responses to chronic stress include– dysregulation in production of catecholamines (epinephrine, norepinephrine),

adrenocorticotropin, cortisol, growth hormone, and prolactin.

Cytokines, particularly IL-6, stimulate corticotrophin-releasing hormoneand HPA-axis activity, increasing plasma adrenocorticotropin hormone and cortisol (Hellhammer 1997; Kirschbaum 1995; Ockenfels 1995; Seeman 1997).

Frequent activation of the glucocorticoid receptor by cortisol can lead to – blunted glucocorticoid response (Miller et al. 2002),– increased nuclear factor-κB signaling (Miller et al. 2008), and – dysregulated catecholamine production (Glaser and Kiecolt-Glaser 2005).

Viltart et al 2007

Impacts on common physiologic systems

Both early childhood environmental exposures and stress-related catecholamines affect Th1–Th2 balance (Umetsu 2002).

Psychological stress (Epel 2004), polycyclic aromatic hydrocarbons, cigarette smoke (Adcock 2005), and ozone (Fugisawa 2005) affect oxidative stress, which is linked to asthma and COPD (Rahman 2000).

Both stress and diesel exhaust particles are associated with elevated cytokines (e.g., IL-2, IL-6, and local IgE in nasal mucosa) (Diaz-Sanchez 2000; Nel 2001).

Stress may alter permeability of bodily membranes (eg brain) to chemical exposures, facilitating combined and synergistic effects of stressors and pollution on many bodily systems. (Sinton et al. 2000)

Key Issues Need to be Addressed

Careful attention to stress measurement

Relative temporality in stress and pollution exposures.

Spatial correlations among social and physical exposures

Pollution and pollution sources as psychosocial stressors

Careful attention to stress measurement

stress process three phases: a) the stressor (i.e., any event, condition, or external stimuli

posing a physical or psychological challenge),

b) stress appraisal (i.e., how one experiences, perceives, or interprets the event), and

c) stress response (e.g., psychological and physiologic sequelae).

Newer measures emphasize later stages of the stress process.

– (glucocorticoid resistance (Miller 2008), C-reactive protein(Miller G, 2012), tumor necrosis factor-α may capture chronic stress in rats.

Relative temporality in stress and pollution exposures

social stressors must precede or be contemporaneous with pollution exposures to plausibly modify their effects.

temporal exposure misclassification– if stress exposure occurs after or very late in a pollution

exposure interval, interpreting observed interactions is problematic.

– if perceived stress is stable over time, the report will accurately reflect stress during the hypothesized period of susceptibility.

– if perceived stress varies over the period, temporal misclassification may significantly confound results

Spatial correlations among social and physical exposures

accurate fine-scale exposure assessment for both stress and pollution is critical.

GIS-based exposure models should be validated to the spatial extent of the exposure in each cohort

spatial patterns in stressors and pollution should be carefully considered to avoid spatial misclassification and confounding.

– eg individuals living closer to highways likely have higher pollution and noise exposures than do other community residents but are not necessarily more exposed to violence or family stress.

Pollution and pollution sources as psychosocial stressors

– neighborhood pollution sources, including highways, power plants, and smokestacks, can send strong messages to residents about the value of their health and well-being (Bullard 1990).

– in residents, with negative health consequences, perceived air quality can also be influenced by disease status (Forsberg et al. 1997, Piro et al. 2008).

– difficult to distinguish health effects produced by the physical aspects of air pollution from its psychosocial health effects in communities near toxic sites (Elliot et al. 1993; Eyles et al. 1993),

– Important to separate both pollution-derived effects from those of other spatially correlated stressors, or to establish directionality.

Are there critical periods for stress and pollution exposures across the life course?

Stress can be toxic at any age, but there may be critical periods, such as during early immune development, when it is particularly influential in shaping future susceptibility and disease risk (Evans and English 2002).

Critical periods for stress and pollution exposures across the life course

Maternal SES and depression stress exposures in young children children’s stress hormone levels (Lupien et al. 2000).

Maternal stress during pregnancy immune function and health in neonates (Weiss and Bellinger 2006).

Maternal air pollution exposures low birth weight (Gouveia et al. 2004) later childhood respiratory disease risk.

Stress exposures during development permanent impact on neuroendocrine, immune, metabolic, and growth processes (Cicchetti and Walker 2001; Viltart 2007; McEwen 2008).

Viltart et al 2007

Early Life Adolescence Adulthood Later Life Senescence

Conceptual Model

Social Environment (eg SES, minority status,

exposure to violence,

parental job insecurity)

Physical Environment (eg outdoor & indoor air quality,

water quality, food contaminants,

chemical exposures

Psychological

Responses (eg perceived

stress, depression,

anxiety

Behavioral

Responses (eg smoking,

sedentary

behavior, diet)

Biological

Responses (eg inflammation,

altered methylation,

glucose control)

Health

(eg respiratory, reproductive, cardiometabolic

outcomes, child development and growth

Environmental

hazards &

pollutants

Exposure

Internal dose

Biologically

effective

dose

Social and Physical

Environment

Nutrition Environmental

Pollutants

Psychosocial

Pregnancy

Physical Development

Prenatal Growth &

Cognitive &

Behavioral Skills

Respiratory Function

& Development

Stress & Other

Factors

Postnatal Growth & Physical

Development

Other Health Endpoints

Need for new pregnancy – birth cohorts specifically designed to study interactions among childhood social adversity and environmental factors on

disease development and prevention

Conclusions

There is tremendous potential, and work still to be done, in understanding combined effects of social and physical environmental exposures.

Accurate characterizion of both social and physical exposures must be performed carefully, especially in light of potential confounding across the exposures, before analyzing and interpreting interactions.

– Temporal relationships between stressors and pollution; – spatial colinearity across exposures; – age-related susceptibility and critical periods; – distinctions between processes related to illness etiology and exacerbation

Scientists in Europe need to work toward a clearer, deeper understanding of complex effects among social and physical environmental exposures on health.

Thank You For Your Attention

Jack P. Shonkoff, MD, Thomas Boyce, MD, Bruce S. McEwen, PhD

Neuroscience, Molecular Biology, and the

Childhood Roots of Health Disparities

Building a New Framework for Health Promotion

and Disease PreventionA 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

2 ways—either by cumulative damage over time or by the biological embedding

of adversities during sensitive developmental periods. In both cases,

there can be a lag of many years, even decades, before early adverse experiences

are expressed in the form of disease. From both basic research and

policy perspectives, confronting the origins of disparities in physical and mental

health early in life may produce greater effects than attempting to modify

health-related behaviors or improve access to health care in adulthood.

JAMA. 2009;301(21):2252-2259

POLICY STATEMENT

Early Childhood Adversity, Toxic Stress, and

the Role of the Pediatrician: Translating

Developmental Science Into Lifelong Health

PEDIATRICS Volume 129, Number 1, January 2012