4

Environmentally Induced Gene Expression

Mechanistic understanding of pathways to disease and preservation of good health necessitates the study of environmentally induced gene expression. A substantial body of research reveals that specific genes can be expressed at different times in an organism's life. Whether a particular gene is expressed and the degree to which it is expressed depend strongly on the environmental conditions experienced by the organism. Such gene expression is implicated in both positive and negative health effects.

Vulnerability and resistance to disease are strongly influenced by genetic endowment and environmental conditions during early periods in development (Coplan et al., 1996; Lui et al., 1997; de Kloet et al., 1998; Laban et al., 1995; Ladd et al., 1996; Levine et al., 1967; Meaney et al., 1991; Plotsky and Meaney, 1993; Seckl and Meaney, 1993). At each stage, development is promoted by the activation of specific genes that regulate cellular activity, migration, and differentiation. This occurs, however, within environmental contexts that shape the processes underlying various stages of an organism's development. At its most fundamental level, development is a constant interaction between environmental and genetic factors.

Genes exert their influence by encoding proteins. The level of such gene activity, however, is a regulated process. As molecules, genes are subject to regulation by intracellular factors that, in turn, are a reflection of environmental factors. Neither genes nor environment dominates development; rather there is continual interaction between genes and the environ-



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New Horizons in Health: An Integrative Approach 4 Environmentally Induced Gene Expression Mechanistic understanding of pathways to disease and preservation of good health necessitates the study of environmentally induced gene expression. A substantial body of research reveals that specific genes can be expressed at different times in an organism's life. Whether a particular gene is expressed and the degree to which it is expressed depend strongly on the environmental conditions experienced by the organism. Such gene expression is implicated in both positive and negative health effects. Vulnerability and resistance to disease are strongly influenced by genetic endowment and environmental conditions during early periods in development (Coplan et al., 1996; Lui et al., 1997; de Kloet et al., 1998; Laban et al., 1995; Ladd et al., 1996; Levine et al., 1967; Meaney et al., 1991; Plotsky and Meaney, 1993; Seckl and Meaney, 1993). At each stage, development is promoted by the activation of specific genes that regulate cellular activity, migration, and differentiation. This occurs, however, within environmental contexts that shape the processes underlying various stages of an organism's development. At its most fundamental level, development is a constant interaction between environmental and genetic factors. Genes exert their influence by encoding proteins. The level of such gene activity, however, is a regulated process. As molecules, genes are subject to regulation by intracellular factors that, in turn, are a reflection of environmental factors. Neither genes nor environment dominates development; rather there is continual interaction between genes and the environ-

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New Horizons in Health: An Integrative Approach ment. Phenotype emerges as a function of this constant dialogue, and any effort to ascribe percentage values to isolated variables is likely to be biologically meaningless. The critical questions in this arena concern gene expression. Studies of gene expression focus on the regulation of gene activity and the mechanisms of gene-environment interactions. The human genome project and the recent development of microarray chip technologies offer researchers remarkable tools for examining the development of vulnerability or resistance to disease. Microarray chips are thin wafers, approximately the size of a dime, containing a densely packed, orderly arrangement of thousands of different probes, utilized for matching known and unknown DNA samples. The technology monitors an entire genome on a single chip, thereby facilitating the detection of gene expression with unprecedented resolution (Ekins and Chu, 1999; Schena, 2000). Realizing the full potential of whole genome analyses will require multidisciplinary research projects that integrate molecular biology with physiology and the behavioral and social sciences. As modern genetics identifies individual or multiple genes associated with many human diseases, such advances will only underscore the importance of understanding the environmental factors that regulate expression of these and other genes. Scientifically, the key task is to define the pathways that lead to disease. This requires understanding first how genes and related factors might be associated with the onset of particular disease outcomes and, second, tracking relevant mediating conditions. The behavioral and social sciences are essential to advancing knowledge of these environmental conditions. Full explication of health pathways thus hinges on integrative multidisciplinary research. In the subsections that follow we present examples illustrative of the current evidential base that connects behavior and the social environment to gene expression (direct and indirect) and subsequent pathways to health outcomes. As a collectivity, these examples represent a coarse-grained description of what is, in fact, a dynamic process of interrelationships between social and physical environments and complex patterns of gene expression that operate over the entire lifetime of different organisms. The examples are each suggestive of new research directions that, if pursued, would notably enhance understanding of pathways to health outcomes. GENE EXPRESSION AND PRENATAL DEVELOPMENT Prenatal life represents a period of cell division and differentiation, the result of which is tissue formation and function. Development is costly in metabolic terms, requiring massive amounts of energy reserves to fuel the growth of bone, muscle, brain cells, and so on. The mother is the sole

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New Horizons in Health: An Integrative Approach source of nutrients for this development, and the interplay between the mother and the fetus is reflected in placental function. Demanding conditions experienced by the mother are transmitted to the fetus through endocrine and nutritional signals. These signals result in both short-term and long-term changes in gene expression in the fetus (Roberts and Redman, 1993; Wadhwa, 1998). Thus, the origins of adult disease are often found in prenatal life. An example of this phenomenon, where behavioral characteristics of the mother are also relevant is interuterine growth retardation (IUGR; Sattar et al., 1999; de Onis et al., 1998, Gülmezouglu et al., 1997). It is estimated that genetic mutations account for approximately 10 percent of the cases of IUGR. The remainder of the cases are due to a wide range of environmental conditions, including maternal smoking, serious infection, malnutrition (especially protein deficiency), excessive alcohol consumption, abuse of drugs, and extreme maternal stress (Kramer, 1987a, b). Each of these risk factors is associated with increased risk of high levels of glucocorticoids in the mother. Glucocorticoids inhibit insulin-like growth factor (IGF) gene expression, as well as the action of IGF (de Kloet et al., 1998). They also increase the production of IGF-binding protein 1 (IGF-1), which serves to biologically inactivate IGF. Both conditions impair development and contribute to the emergence of IUGR. The alterations in gene expression accompanying IUGR increase the sensitivity of hypothalamic-pituitary-adrenal (HPA) and sympathetic responses to stress in later life (Ladd et al., 1996). The elevated levels of stress hormones, in turn, increase vulnerability of the individual to diabetes and heart disease. An important challenge for future research is to understand how psychosocial adversity over the life course of low-birth-weight babies—having experienced IUGR—is related to subsequent processes of gene expression that culminate in diabetes, coronary heart disease, or both. PERSONAL TIES AND GENE EXPRESSION IN MIDLIFE Increasing evidence documents the role of personal ties on gene expression in midlife. For example, the genetic transcription responsible for the production of lymphocyte growth hormone (L-GH) is, in part, age related, as L-GH secretion decreases with increasing age (Nordin and Proust, 1987; Krishnaraj et al., 1998). However, extended disruption of personal ties also modulates L-GH levels. Caregivers of spouses with Alzheimer's disease have markedly suppressed L-GH concentrations compared to age- and gender-matched controls (Wu et al., 1999). The transduction process by which disruption of personal ties modulates growth hormone (GH) messenger RNA (mRNA) is most likely to involve stress hormones such as adrenocoricotropic hormone (ACTH), cortisol, and catecholamines (Kiecolt-Glaser

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New Horizons in Health: An Integrative Approach et al., 1997). Reduced levels of GH consequential to a disruption of personal ties can be involved in immune system function. In particular, current evidence suggests that GH promotes the efficacy of lymphocytes in responding to antigens, with its route of action being via the TH-1 and TH-2 helper cytokine system (Wu et al., 1999). Research is needed to clarify the details of this proposed process, including whether these perturbations in immune system parameters translate to downstream health outcomes. In addition, we need to understand how cumulative adversity in a variety of interpersonal relationships is connected to processes of gene expression that may culminate in impaired immune function and thereby contribute to a range of disease outcomes. ANIMAL MODELS AND THE CONSEQUENCES OF MOTHER-CHILD INTERACTIONS Although the above examples focus on human populations and important research agendas that follow from them, animal models have been and will continue to be a main route to achieving deeper understanding of mechanisms of gene expression. For example, the role and character of mother-child interactions that influence neural development have recently been studied in detail in rats (Lui et al., 1997; Caldji et al., 1998; Francis et al., 1999). Specifically, there are two forms of maternal behavior in the rat—licking and grooming of pups (LG) and arched-back nursing (ABN)—that appear to regulate the development of stress reactivity in the offspring. As adults the offspring of mothers exhibiting high levels of LG-ABN care showed reduced plasma ACTH and corticosterone responses to restraint stress. These animals also show significantly increased hippocampal glucocorticoid receptor mRNA expression, enhanced glucocorticoid negative feedback sensitivity, and decreased hypothalamic corticotropin-releasing hormone mRNA levels. The results of these studies suggest that the behavior of the mother toward her offspring can program the expression of genes regulating neuroendocrine response to stress in adulthood (Lui et al., 1997). Support for this claim derives from the fact that as adults the offspring of low LG-ABN mothers exhibit increased fearfulness relative to offspring of high LG-ABN mothers (Caldji et al., 1998). They also show increased corticotropin-releasing factor (CRF) receptor levels in the locus coeruleus and decreased central benzodiazepine receptor levels in the basolateral and central nucleus of the amygdala, as well as increased CRF mRNA expression in the central amygdala. Predictably, stress-induced increases in levels of norepinephrine in the paraventricular nucleus of the hypothalamus were significantly higher in the offspring of low LG-ABN mothers (Francis et al., 1999). These are all neurophysiological signs of elevated reactivity to stress in adulthood.

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New Horizons in Health: An Integrative Approach It may seem surprising that rather subtle variations in maternal behavior have such profound impact on development. However, for a rat pup, the first six weeks of life do not hold a great deal of stimulus diversity. Stability is the theme of the burrow, and the social environment in the first days of life is defined by the mother and the littermates. The mother then serves as the primary link between the environment and the developing animal. Following on these results, an important line of research, linked to pathway studies in humans that are the core of this report, is identification of the features of rat life histories and their relationship to gene expression that contribute to downstream health outcomes. INTERGENERATIONAL TRANSMISSION OF BEHAVIOR Another line of recent animal research having profound implications for future investigations in humans centers around evidence that individual differences in maternal behavior are transmitted across generations (in both rats and nonhuman primates). For example, in rats the female offspring of high LG-ABN mothers show significantly more licking and grooming and arched-back nursing than female offspring of low LG-ABN mothers (Francis et al., 1999). In rhesus monkeys there is clear evidence for inter-generational transfer of rejection of infants by mothers. The rate of rejection of infants by mothers correlated with the rejection rates of their mothers (Suomi, 1987; Suomi and Levine, 1998). In vervet monkeys, daughters reared by mothers who consistently spent a large amount of time in physical contact with their offspring became mothers who were similarly more attentive to their offspring (Fairbanks, 1989). An important complement to these findings is evidence indicating that specific environmental events can alter trajectories of development not only in the affected offspring but also into the next generation (Francis et al., 1999). For example, biological offspring of low LG-ABN mothers cross-fostered onto high-LG-ABN mothers are indistinguishable from the natural progeny of high-LG-ABN mothers in terms of behavioral measures of fearfulness or of HPA axis response to stressful experiences. In addition, these behavioral effects are reflected in corresponding changes in CRF gene expression in the hypothalamus and amygdala. Moreover, in adult females of both the cross-fostered and natural progeny groups, their maternal behavior was typical of high-LG-ABN mothers. Similarly, the behavior of adult offspring of high-LG-ABN mothers reared by low-LG-ABN dams resembled that of the normal offspring of low-LG-ABN mothers. An example relating directly to predisease pathways concerns cross-fostering between borderline hypertensive rats (BHR) and wild-type WKY mothers (Gouldsborough and Ashto, 1998; Sanders and Gray, 1997; Myers et al., 1989). The starting point for this investigation is the introduc-

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New Horizons in Health: An Integrative Approach tion of the spontaneously hypertensive rat (SHR), a strain bred for the appearance of hypertension in adolescence. While the selective breeding implies a genetic background, the expression of the hypertensive trait is also influenced by epigenetic factors. SHR pups reared by wild-type WKY mothers do exhibit hypertension to the extent of kin reared by SHR dams. However, BHR—a hybrid formed by SHR-WKY matings —pups reared by WKY mothers do not express the spontaneous hypertensive phenotype. An important future research priority is to determine whether these effects are associated with changes in the expression of genes that regulate blood pressure. Extending the discussion to humans, it should be asked which supportive environments for which groups of people induce gene expression that reduces the risk of hypertension. PLASTICITY OF GENETIC TRAJECTORIES The above cross-fostering examples also serve to illustrate the adaptive value of plasticity. If a genetically determined trajectory is not advantageous, then the ability to adjust in response to a new environmental signal would have an adaptive value. These effects are not so readily seen in the wild, since low-LG-ABN rats are typically reared by low-LG-ABN mothers. Similarly in mice, BALBc pups—a strain that is normally very fearful with elevated HPA response to stress—are reared by BALBc mothers. Because parents provide both genes and environment to their biological offspring, these factors enhance the disadvantageous consequences seen in adulthood. For this reason, knowing that a mouse has a BALBc pedigree is usually sufficient to predict a high level of timidity in adulthood. BALBc mice cross-fostered to C57 mothers are significantly less fearful and have lower HPA responses to stress (Zaharia et al., 1996; Anisman et al., 1998). These examples emphasize the potential for traits to be modified by environmental interventions. They clarify that gene expression accompanies such interventions; and they emphasize the importance of pursuing analogous studies in humans with a far more diverse set of environmental influences. Having emphasized the impact of parental care, it is important to observe that caring takes place in a great diversity of natural environments and that this added variation is consequential for development and health. Important examples of the joint influence of mother-infant bonding and other environmental factors are studies of Bonnet macaque mother-infant dyads maintained under one of three foraging conditions: low foraging demand (LFD), where food was readily available high foraging demand (HFD), where ample food was available but required long periods of searching; and variable foraging demand (VFD), a mixture of the previous two conditions on an unpredictable schedule (Andrews and Rosenblum, 1994). Prior to the time these conditions were imposed, there were no differences

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New Horizons in Health: An Integrative Approach in the nature of mother-infant interactions. Following a number of months of the experimental conditions, however, there were highly significant differences in mother-infant interactions. The VFD condition was clearly the most disruptive. Mother-infant conflict increased under the VFD condition. Infants of mothers housed under these conditions were significantly more timid and fearful. The infants showed signs of depression commonly observed in maternally separated macaque infants, even while the infants were in contact with their mothers. As adolescents, infants reared in the VFD conditions were more fearful and submissive and showed less social play behavior. More recent studies (Coplan et al., 1996, 1998; Rosenblum et al., 1994) show that, as adults, monkeys reared under VFD conditions have increased levels of CRF. Increased central CRF drive suggests altered noradrenergic and serotonergic responses to stress, exactly as seen in adolescent VFD-reared animals. An important research objective is to ascertain whether these traits are transmitted to the next generation. Researching predisease pathways, it is also important to document the later-life health profiles of VFD-reared and -maintained macaques in comparison with macaques reared in either of the stable environments, LFD or HFD. WHOLE-GENOME ANALYSES All of the studies described above provide a coarse picture of the interrelationships between environmental fluctuations, behavior, physiological response, and gene expression over the life course. To date, a limiting factor has been the absence of a technology for carrying out whole-genome studies coupled with the unavailability of whole-genome data. This situation is changing rapidly. Whole-genome data are currently available for a diversity of organisms (e.g., yeast, M. tuberculosis, H. influenza, drosophila, C. elegans), including humans. 1 The nematode C. elegans and drosophila are among the more prominent nonhuman organisms where behavioral studies have also been carried out. In addition, the development of microarray chip technology (Fodor, 1997; Cho et al., 1998; Ekins and Chu, 1999; Schena, 2000) has made studies of gene expression feasible with unprecedented precision. Over the next decade it should be possible to study environmentally induced gene expression as a dynamic process from conception to death. The greatest progress and short-term payoff are likely to be in animal studies (Lee et al., 1999); however, studies in humans are already clarifying pathways to cancers (Golub et al., 1999; Alon et al., 1999) and pulmonary fibrosis (Kaminski et al., 2000) with unprecedented 1   The data are available electronically at www.nhgri.nih.gov/PMGifs/Genomes/allorg.html.

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New Horizons in Health: An Integrative Approach precision. This implies that many of the questions documented in this report regarding predisease pathways, positive health, inequalities, and community-level influences should be answerable in animal populations down to the level of gene expression. Such studies should stimulate a host of investigations on human populations that will provide a deeply more integrated understanding of pathways to diverse health outcomes. RECOMMENDATIONS NIH should support integrative research aimed at understanding the role of environmentally induced gene expression in disease etiology and promotion of health. This initiative should include: studies that combine environmental manipulations with physiological and molecular assessments to provide refined understanding of conditions leading to dysfunction and the mechanisms that preserve allostasis; studies that explore in animal models the relationships between chronic stress, interactions among intervening systems (e.g., HPA axis and immune systems), and health outcomes; initiation of studies using microarray chip technologies to monitor gene expression associated with a broad range of environmental manipulations; development of animal housing facilities, particularly for rodents, that more closely approximate species-specific natural habitats. REFERENCES Alon U , Barkai N , Notterman DA , Gish K , Ybarra S , Mack D , Levine AJ. 1999 “Patterns of gene expression revealed by clustering analysis of tumor and normal colon tissues probed by oligonucleotide arrays” Proceedings of the National Academy of Sciences of the United States of America 96 : 6745-6750 . Andrews MW , Rosenblum LA. 1994 “The development of affiliative and agonistic social patterns in differentially reared monkeys” Child Development 65/5 : 1398-1404 . Anisman H , Zaharia MD , Meaney MJ , Merali Z. 1998 “Do early-life events permanently alter behavioral and hormonal responses to stressors?” International Journal of Developmental Neuroscience 16/3-4 : 149-164 . Caldji C , Tannenbaum B , Sharma S , Francis D , Plotsky PM , Meaney MJ. 1998 “Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat” Proceedings of the National Academy of Sciences of the United States of America 95 : 5335-5340 . Cho RJ , Fromont-Racene M , Wodicka L , Feierbach B , Stearns T , Legrain P , Lockhart DJ , Davis R. 1998 “Parallel analysis of genetic selections using whole genome oligonucleotide arrays” Proceedings of the National Academy of Sciences of the United States of America 95 : .

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