Conceptualizing Child Health Disparities: A Role for Developmental Neurogenomics

AUTHOR: Darlene D. Francis, PhD abstract Department of Psychology, and School of Public Health, Helen Biological, psychological, and social processes interact over a lifetime Wills Institute, University of California, Berkeley, California to influence health and vulnerability to disease. Those interested in KEY WORDS studying and understanding how and why racial/ethnic and social dis- disparities, development, stress, parities emerge need to focus on the intersection of these processes. ABBREVIATIONS Recent work exploring molecular epigenetic mechanisms of ex- SES—socioeconomic status pression (in as well and other mammalian systems) has pro- HPA—hypothalamic-pituitary-adrenal vided evidence demonstrating that the is subject to regulation CRF—corticotropin-releasing factor by surrounding contexts (eg, cytoplasmic, cellular, organismic, social). The views presented in this article are those of the author, not The developing stress axis is exquisitely sensitive to regulation by so- the organizations with which she is affiliated. cial forces represented at the level of the epigenome. Old assumptions www.pediatrics.org/cgi/doi/10.1542/peds.2009-1100G about an inert genome are simply incorrect. Epigenetic processes may doi:10.1542/peds.2009-1100G provide the missing link that will allow us to understand how social and Accepted for publication Jul 20, 2009 political conditions, along with individual subjective experiences, can Address correspondence to Darlene D. Francis, PhD, University directly alter gene expression and thereby contribute to observed so- of California, 3210 Tolman Hall, MC 1650, Berkeley, CA 94720- 1650. E-mail: [email protected] cial inequalities in health. Developmental neurogenomics may provide PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). the direct link between the biological and social/psychological worlds. These biological mechanisms of plasticity (at the level of gene expres- Copyright © 2009 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The author has indicated she has no sion and regulation) may play a profound role in how we conceptualize financial relationships relevant to this article to disclose. health inequalities by informing our concepts regarding the somati- zation or embodiment of social inequalities. Pediatrics 2009;124: S196–S202

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Biological, psychological, and social expressed. Epigenetic processes may are transmitted across generations, processes interact over a lifetime to be the key to understanding how are different “versions” of a influence health and vulnerability to forces distal to an individual, such as gene (they exist in 2 forms; dominant disease. A wealth of epidemiologic social and political conditions, along or recessive), and a given genotype is data have documented the relation- with more proximate individual (sub- related to an observable . ship between socioeconomic status jective) experiences can directly alter This view of has expanded (SES) and health, with low-SES groups gene expression and thereby contrib- dramatically since the early 1900s, yet faring most poorly across multiple ute to observed social inequalities in most scientists who do not work at the health-outcome measures.1 The proba- health. The very recent and powerful level of the genome have had little or bilistic relationship between social new results demonstrating that the no exposure to recent findings in the phenomena and biological vulnerabil- epigenome is subject to environmental field. As a consequence, we remain ity seems to be in direct contrast to the regulation could provide the direct link saddled with the antiquated central commonly shared belief that the fixed between the biological and social or dogma that (1) the flow of information genome (or genotype) plays a larger psychological worlds. Understanding is unidirectional, from to envi- “deterministic” role in health out- how genes are differentially regulated ronment, and (2) biological vulnerabil- comes. Indeed, a common approach to by experience will play a profound role ities are classically inherited (in con- understanding disparities by explor- in how we conceptualize health ine- trast to being created by “vulnerable” ing “social” and “biological” factors as qualities by informing our concepts of environments or experience).2 This independent agents divorced from one the somatization or embodiment of so- limited perspective of the genome has another has been extremely limiting. cial inequalities. As our knowledge of had a large influence on the theoreti- The ubiquitous study of gene ϫ envi- epigenetic processes grows, so too cal framework of many academic dis- ronment interactions provides a ready does our capacity to develop early-life ciplines. Table 1 shows the units of example. The assertion is made that interventions to prevent and mitigate study or focus for some classic aca- vulnerability for a given outcome mea- child health disparities. demic disciplines. sure is caused by the interaction of The number of genes predicted (by mo- genes with environments, the classic PLASTICITY OF THE GENOME lecular biologists and ) to nature-versus-nurture debate. Inher- Ecological models and theories of hu- exist in the genome was far ent in the framing of this equation is an man health that emphasize the inter- higher (ϳ150 000) than the number unacknowledged directionality; genes action of biological, behavioral, and reported (ϳ25 000) in the first draft of come first in time and environments environmental determinants are plen- the Human Genome Project report.3,4 then act on them, resulting in a given tiful. In reality, however, few truly mul- To provide an example, humans and vulnerability. Equally plausible but tilevel research programs or projects the worm Caenorhabditis elegans rarely explored at a molecular or translate at a practical level. For those have a similar number of genes, 20 000 mechanistic level is the hypothesis studying the genome, imagining the to 25 000, despite large differences in that environmental factors are acting ways in which social and societal organism size and complexity. Both on the genome to create differences in forces might alter how genes are reg- species have significantly fewer genes vulnerability (or resilience). The same ulated and expressed seems formida- than the corn plant, which has 40 000.5 variables are factored into the equa- ble. Conversely, those who are inter- Clearly, humans are greater than the tion; however, the function can now be ested in social disparities might find it sum of their genes. The emerging field ϫ described as an environment gene fantastical to assume that a working of epigenetics focuses on the study of interaction. knowledge of biological mechanisms, changes in gene expression that are Recent work exploring molecular epi- such as gene regulation and gene not caused by changes in DNA se- genetic mechanisms of gene expres- expression (ie, genomic plasticity), quence.6 The epigenome consists of sion (in humans and other mammalian might directly inform how they funda- DNA marks and modifications that con- systems) has provided evidence that mentally conceptualize the embodi- trol gene expression.7 The epigenome the genome is subject to regulation by ment of social experience. is innately plastic and can be pro- surrounding contexts (eg, cytoplas- For many social scientists a working grammed or reprogrammed by envi- mic, cellular, nutritional, organismic, knowledge of genetics is limited to a ronmental experiences such as nutri- and sociopolitical). Environments are classical mendelian perspective; genes tion and stress.8–10 These epigenetic capable of regulating how genes are are the physical units of , they mechanisms provide the means

PEDIATRICS Volume 124, Supplement 3, November 2009 S197 Downloaded from www.aappublications.org/news by guest on September 29, 2021 TABLE 1 Focus of Classic Academic Disciplines lead to impairments.14 Increased Academic Discipline Focus Environment “wear and tear” on an organism that is Genetics Gene transmission and genotypes Cell nucleus, DNA subjected to repeated challenge or Molecular and Gene-cell regulation System, cell, RNA, and DNA stress might chronically tax the HPA cellular biology Neuroscience Nervous system and axis and ultimately lead to disease vul- Medicine Individual diseases Individual person nerability (both mental and physical). Psychology and social Behavioral and individual differences Individual person or animal and social psychology space (SES, gender, race) DEVELOPMENTAL PLASTICITY OF Sociology Group processes Individuals in groups Ecology Organisms and their environment Physical world THE STRESS AXIS Public health Health protection, promotion, and Populations restoration The quality of early family-life events Public policy Effects of government decisions and Decision-making bodies can influence the health of human, indecision nonhuman , and other mam- malian offspring throughout their life- times. models provide the best through which social experiences can in mammals. This response governs demonstration of parental calibration fundamentally and profoundly alter the metabolic and cardiovascular re- of the developing stress axis in young the regulation and expression of the sponses to the challenges of everyday animals. In the rat, variations in mater- genome without altering genotypes. stressors and those associated with nal care are associated with the devel- Epigenetic processes are extremely more prevailing chronic stress. opment of differences in behavioral active during early developmental win- During stress, the hypothalamus (in and endocrine responses to stress in dows when a young organism is grow- the brain) releases corticotropin- ing. The epigenome, therefore, is ex- the offspring. Naturally occurring vari- releasing factor (CRF). CRF provokes ations in maternal licking (the largest tremely sensitive to dysregulation the release of corticotropin from the during early development when DNA source of tactile stimulation) are asso- pituitary gland, which, in turn, causes synthesis rates are highest.7 ciated with the development of individ- the release of glucocorticoids from the ual differences in the HPA axis and be- The environment column in Table 1 12 adrenal gland. The highly catabolic havioral responses to stress in the helps in visualizing and understanding glucocorticoids act in synergy with offspring.15,16 As adults, offspring of how environmental characteristics at catecholamines to produce lipolysis, high-licking mothers are behaviorally every level (individual, family, commu- glycogenolysis, and protein catabo- less fearful and exhibit a more modest nity, etc) can potentially affect genome lism, which result in increased blood HPA-axis response to stress than off- regulation. Again, the salient role of glucoses. These processes contribute spring of low-licking mothers.16 High- early life experiences is evident. We be- to the survival of an organism during licking adult offspring have lower gin to mechanistically understand how stress, in part by increasing the avail- corticotropin and corticosterone re- both biological vulnerability and resil- ability of energy substrates.13 sponses after an acute challenge or ience can emerge from differences in stressor than low-licking adult off- the social experience. Prolonged exposure to elevated stress hormones, however, can become prob- spring. These responses are believed STRESS AXIS AS A OF lematic. Glucocorticoids, along with to be mediated, in part, by differential VULNERABILITY OR RESILIENCY catecholamines, promote the suppres- regulation and expression of the glu- Stress is a risk factor for several ill- sion of anabolic processes, muscle at- cocorticoid receptor gene in the brain. nesses such as cardiovascular dis- rophy, decreased insulin sensitivity, Extremely relevant is the plasticity in- ease, type 2 diabetes, and depres- hypertension, amenorrhea, impo- herent in the quality of parent- sion.11 The pathways through which tence, and impaired tissue repair. Cog- offspring interactions. The simple pro- stressful events can promote the de- nitive and emotional states also cedure of rat pup cross-fostering at velopment of such divergent illnesses change during stress.11 CRF release in birth is sufficient to reverse the pheno- and compromised health seem to be the brain activates pathways that en- types described above. Rat pups born mediated by activation of the same hance vigilance when the organism is to a high-licking mother but reared by systems that ensure survival. Activa- challenged. Again, activation of these a low-licking mother exhibit stress re- tion of the hypothalamic-pituitary- pathways is quite adaptive under activity as adults that are indistin- adrenal (HPA) axis in response to acute challenge or stress, but contin- guishable from that of offspring born stress is a basic adaptive mechanism ued activation of these circuits can to and reared by a low-licking mother.

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Conversely, offspring born to a (mediated by epigenetic processes) al- SES AND THE STRESS RESPONSE low-licking mother but reared in a lows us to retreat from the discourse Epidemiologic studies have identified a high-licking and grooming maternal that focuses on biological or psycho- graded, continuous association be- environment exhibit stress-reactivity social vulnerabilities. An understand- tween socioeconomic conditions and profiles of offspring born to and ing of developmental neurogenomics morbidity in adults and children of reared by a high-licking mother.17,18 allows us to transcend this debate widely varied SES levels.32 This gradi- The simple environmental intervention and readily observe how the social ent of SES-health relationships leads (adoption) affected not only the exist- experience of chronic and pervasive to differences in morbidity at all SES ing generation of animals growing up racism and discrimination is experi- levels. People in each class have but also subsequent generations. enced somatically as a chronic stres- poorer health outcomes than those in The cross-fostering of offspring early sor with inevitable deleterious out- the class just above theirs and better in life alters adult behavioral, hor- comes. Blacks have higher disease outcomes than those in the class just monal, and neurobiological profiles. rates relative to whites even when con- below. This gradient suggests a nu- 25,26 This finding suggests that the quality of trolling for SES. The “weathering anced link between SES and health maternal care early in life is directly hypothesis” suggests that racial dis- that extends beyond the common ef- involved in the development and pro- parities exist with respect to the bur- fects of extreme poverty, which often gramming of the HPA axis. Events or den of stressors that accumulate over includes poor nutrition, inadequate 25 experiences that alter maternal care the lifetime. Those individuals who housing, environmental exposures, are thus capable of directly altering are subjected to the greatest levels of and lack of access to health services. the development of the offspring. High- racial discrimination (ie, stress) have One plausible explanation for the SES- 27,28 licking mothers (characterized while the worst mental health outcomes. health association is that chronic rearing a first litter) subjected to If we approach the question of racial/ activation of the stress response stress during gestation for a second ethnic disparities in health from the (stemming from the experiences of ad- litter exhibit decreased licking profiles perspective of developmental neuro- versity that accompany lower and dis- , we can begin to understand once offspring are born. Thus, these advantaged social positions) could how different lived social experiences 22,33,34 offspring are reared under low-licking compromise health. This hypoth- leave their epigenomic imprint on an conditions and, as adults, exhibit exag- esis is consistent with evidence that organism. The genotype is fixed. What gerated stress-reactivity profiles.19 relates lower SES with elevated basal remains plastic, and therefore sub- activation of the stress axis in chil- Early postnatal experiences can cali- ject to environmental regulation, is dren35–37 and heightened neural reac- brate the developing brain and neu- the epigenome. If we hypothesize that tivity to stressful challenges.38–41 An as- roendocrine axis in expectation of fu- racial discrimination is capable of di- sociation of stress with subordinate ture similar environments. The HPA rectly altering the epigenomic pro- social positions is also consistent with axis profiles described above persist files of genes that are important to the the previous finding that subjective es- into adulthood and old age if environ- stress response, we can then predict timates of social class might be a 20,21 mental conditions remain stable. that targeting and ameliorating dis- stronger predictor of health outcomes Very recent findings using the labora- crimination and racism should have than objective indicators, such as job tory rat as a model report that differ- an equally direct, potent, and protec- status, income, or wealth.42–44Previous ences in early life events are specifi- tive effect on the stress-axis epi- research has also shown that domi- cally altering the epigenetic processes genome. This hypothesis would ex- nance status in primate social hierar- that regulate expression of the glu- tend to other socially disadvantaged chies is similarly associated with cocorticoid receptor in the brain. The groups subject to the stress associ- health, even among captive animals genotypes of the developing animals ated with discrimination.29–31 Rather with equal access to food, open envi- are intact; however, their epigenomes than engaging in the nature-versus- ronments, and veterinary care.35,45–47 22–24 are dramatically altered. nurture debate concerning race as a Stress and adversity among young genetic or social construct, we now children of low SES come in many RACIAL/ETHNIC DISPARITIES AND define race as an epigenomic con- forms and varieties. Poor children are THE STRESS RESPONSE struct in which genotype and the so- routinely exposed to neighborhood vi- Conceptualizing race as a product cially experienced world are perpetu- olence; disorganized, dysfunctional of environment ϫ gene interactions ally entwined. schools; family turmoil; household

PEDIATRICS Volume 124, Supplement 3, November 2009 S199 Downloaded from www.aappublications.org/news by guest on September 29, 2021 FIGURE 1 Social calibration of the stress response. (Figure courtesy of W. T. Boyce, MD.) chaos; and parental divorce.48 Among and ameliorating child health dispari- cesses are embodied and represented the most proximate stressors in the ties necessarily represent a diverse biologically free us from the con- lives of poor children are the common group of professionals with broad no- straints of having to defend a biolog- experiences with harsh, unresponsive, tions of what matters most. By default, ical or psychosocial argument to ex- and authoritarian parenting. Children most of us have inherited the theoret- plain disparities in health. The of lower SES experience a dispropor- ical framework of our academic disci- evidence at hand overwhelmingly dem- tionate share of conflictive and puni- plines (captured in Table 1). We tend to onstrates that the biological and psy- tive parent behavior, even in infan- focus on the levels of analyses most chosocial arguments are, indeed, one cy.48–50 Disadvantaged homes produce familiar to us. We acknowledge that and the same. Moreover, because the not only more experiences with nega- disparities arise from the intersection- genotype of an organism is fixed and tive parenting but also fewer positive ality and interactions of the genome immutable, all interventions should be parent-child experiences. Class-based with experiences as they occur in time; targeted to optimize those variables differences in children’s disciplinary, however, we rarely get to study them. and features that promote plasticity. socioemotional, cognitive, and linguis- The calibration and regulation of the For policy makers it should now be tic experiences with primary caregiv- stress axis in response to social forces clear that efforts to eliminate or mini- ers are demonstrably related to brain provides us the opportunity to directly mize social inequalities (caused by development, particularly in the neu- investigate this intersection. Develop- racism, SES, and class) would have di- ral structures that are tied most mental neurogenomic processes con- rect biological effects on an individual. closely to the ontogeny of reasoning tribute to disparities in child health Moreover, interventions or programs capacity and language. Specifically, and well-being. Chronic stressors em- that target the earliest developmental these experiences are linked to the ex- bedded in proximate family experi- windows in the young child may pre- ecutive functions involved in strategic ences (such as maternal depression vent or significantly attenuate the cu- planning and the regulation of emotion and decreased parental care) are mulative effects of social disadvan- and social behavior.51 Figure 1 illus- themselves subject to regulation by ul- tage, which we know emerge over the trates how broader social forces such timate forces, including economic life span. Funding mechanisms rarely as SES can modulate parenting pro- hardship, neighborhood safety, and files, which are critically involved in target these most biologically plastic high-quality housing. Proximate- and calibrating the stress axis in the devel- and labile developmental windows. In- ultimate-level forces are biologically oping child. We see how larger social formed by biological mechanisms calibrating critical developmental pro- forces in concert with more proximate such as those described in this article, cesses in children, thereby influenc- social factors are able to impinge on policies that create economic, social, ing their vulnerability to and risk of the developing child to create biologi- or political change can all fundamen- and illness. A developmen- cal vulnerabilities (another example of tally affect the biological development tal neurogenomics approach makes it an environment ϫ gene interaction).52 of a single individual as well as whole possible to begin conceptualizing and populations. To grasp a full under- A ROLE FOR DEVELOPMENTAL understanding childhood health dis- standing of why and how social dis- NEUROGENOMICS IN DISPARITIES parities from multiple perspectives parities emerge, we need to collec- RESEARCH? and dimensions. tively move beyond the false dichotomy Researchers, clinicians, and practitio- A fundamental understanding of the of the biological-psychosocial divide. ners with an interest in understanding mechanisms by which social pro- An understanding of developmental

S200 FRANCIS Downloaded from www.aappublications.org/news by guest on September 29, 2021 SUPPLEMENT ARTICLE neurogenomics provides us with the research,53 policy,54 and practice.55 intersect to create vulnerability (or tools to do just that. However, educational or training op- resilience). Students taught the fun- portunities that marry the disciplines damental concepts of neuroscience, THE NEXT FRONTIER OF CHILD of neuroscience, molecular biology, developmental genomics, and HPA/ HEALTH DISPARITIES RESEARCH and childhood health disparities are stress-axis function as they relate to Recent advances in the area of devel- virtually nonexistent (at least at the social inequalities and health can take opmental biology and neurogenomics level of graduate education). A peda- the basic biological knowledge they have provided evidence to demon- gogical approach inclusive of basic de- have acquired and immediately trans- strate, mechanistically, how challeng- velopmental biology, molecular biol- late it to disciplines as diverse as pub- ing or compromised early experiences ogy, and neuroscience offered to the lic policy, community health, medicine, can create biological vulnerabilities next generation of health-disparities clinical psychology, social work, and that affect both physical and mental researchers would create a powerful education. By providing the current health outcomes in the developing element for change. A breadth of bio- generation of health-disparities re- child. Shonkoff et al52 have made an logical training early in an academic searchers with a solid background in excellent case for building a new trajectory should serve to “lessen” the relevant biological mechanisms we framework of health promotion and silo-based approaches often used to will, in essence, be cultivating the next disease prevention with neuroscience, address disparities-related research. generation of researchers, practitio- molecular biology, and childhood No longer would the framework be one ners, and policy makers who can roots of health disparities at the core. of biological, psychological, or social readily endorse the assertion that Evidence of this novel agenda is begin- vulnerabilities but, rather, a frame- early adversity can create health ning to emerge at the levels of work focused on how these processes vulnerabilities. REFERENCES

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S202 FRANCIS Downloaded from www.aappublications.org/news by guest on September 29, 2021 Conceptualizing Child Health Disparities: A Role for Developmental Neurogenomics Darlene D. Francis Pediatrics 2009;124;S196 DOI: 10.1542/peds.2009-1100G

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Downloaded from www.aappublications.org/news by guest on September 29, 2021 Conceptualizing Child Health Disparities: A Role for Developmental Neurogenomics Darlene D. Francis Pediatrics 2009;124;S196 DOI: 10.1542/peds.2009-1100G

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