Thomas O'Connor, Ph.D. - US grants

DESCRIPTION (provided by applicant): Experimental animal research strongly implicates prenatal stress in the long-term behavioral/emotional, cognitive, and neuroendocrine disturbance in offspring in a manner suggesting a programming mechanism. Recently reported data suggest that a parallel association may exist for prenatal anxiety in humans. The potential implications of these findings for understanding and preventing mental health problems in children and adults are both obvious and substantial. Basic questions remain, however, about the persistence of effects in humans, the mechanisms underlying the association, and the role of postnatal environmental experiences and genetic factors in accounting for individual variation. This proposal addresses these questions in the context of a unique multidisciplinary prospective, longitudinal study of a large community sample that has been continuously followed since early pregnancy. The study proposes to conduct in-person assessments of approximately 8,000 14 year-olds who have been followed since birth and for whom exposure to prenatal maternal anxiety and postnatal psychosocial adversity has been well-characterized. Data on psychopathology and HPA axis functioning at age 14 will be predicted from the interplay between previously collected data on maternal anxiety in pregnancy, specific psychosocial risks, and polymorphisms for the glucocorticoid receptor genes. The current study would provide a state-of-the-science investigation of prenatal anxiety that will have substantial impact on developmental theory and public health, and build on and extend research into the genetic bases of individual differences in stress vulnerability and psychopathology Specific aims of this research are to a) examine the long-term effects of prenatal anxiety on dimensional and diagnostic measures of psychopathology in early adolescence;b) assess the role of the HPA axis underlying the links between prenatal anxiety on adolescent psychopathology and stress vulnerability;c) test competing hypotheses concerning the processes by which prenatal anxiety has direct, mediated or moderated effects on adolescent psychopathology;and d) test the hypothesis that the effects of prenatal anxiety/stress on behavioral/emotional problems in early adolescence are moderated by genetic risk.

DESCRIPTION (provided by applicant): Literally dozens of animal studies indicate that offspring of prenatally stressed mothers exhibit a wide range of behavioral, physiological, and immunological impairments that persist into adulthood. Research into the mechanisms involved identifies the hypothalamic-pituitary-adrenal (HPA) axis as the most likely mediating mechanism, and further imply that this system may be "set" or "programmed" in utero. The relevance of these findings and of the programming mechanism to humans is unclear. There is now good correlational evidence that prenatal anxiety is associated with child outcomes, but translation from the animal model to humans is far from complete because of lingering questions about the causal nature of this link, the degree to which both behavioral and biological outcomes are affected, and the mechanisms involved. The proposed study will provide much-needed new information in this line of research by investigating causal hypotheses concerning the HPA axis, testing the links with behavioral and immune outcomes, and examining the role of early parent-infant relationship quality as a moderator of the effects of prenatal anxiety. 200 women, one-half of whom meet diagnostic criteria for anxiety, will be followed prospectively;data on psychological and physiological measures of anxiety will be collected on multiple occasions in pregnancy and the postnatal period. Obstetric, immune, cognitive, HPA axis, and behavioral/emotional outcomes in children will be collected at 2, 6, 12, and 16 months postnatally. For data on immune functioning, we will take advantage of naturally occurring immune stresses in the form of Hepatitis B and tetanus, and will document both B and T cell mediated responses. Scientifically, findings from the proposed multidisciplinary, prospective longitudinal study will provide essential data to evaluate the possibility that a "programming" mechanism associated with prenatal anxiety also exists in humans. These data will also carry substantial public health significance, particularly given what is known about the high prevalence of anxiety in pregnancy. Moreover, the detailed focus on immune function means that these observations will extend this research well beyond mental health, and may illuminate further the mechanisms by which early stress exposure influences psyche and soma.

DESCRIPTION (provided by applicant): Many studies demonstrate that stress exposure in childhood is associated with multiple kinds of illnesses in adulthood. The mechanisms underlying these associations are not yet clear, but there is consideration speculation that inflammation and, more broadly, alteration of the immune system from early stress exposure has an etiological role. What has not been established is the extent to which, and the mechanisms by which, early stress exposure has childhood onset effects on the immune system. Research is now needed to translate adult and a sizable experimental animal literature to pediatric samples; results from these studies would fundamentally shape public and clinical health approaches. The proposed study makes use of the Family Life Project (FLP), an ongoing prospective longitudinal study of 1292 children who were selected using epidemiological methods to oversample stress-exposed children. Indicators of innate and adaptive immune function will be collected from detailed developmental visits when the children are approximately 9 years of age and linked with measures of stress, behavior and psychosocial context data dating back to 2 months of age. Several features of the proposed study provide particular leverage for advancing this field of research, including a) a large epidemiologically-derived sample of pre-adolescent children at elevated psychosocial risk who have been carefully studied since infancy, b) detailed study of the innate and adaptive immune systems, and c) detailed assessment of socio-demographic and proximal family stress across the first decade of life that provide leverage for testing hypotheses about the type and timing of stress exposure, and d) examination of glucocorticoid resistance as a mediating mechanism. The research aims are to 1) test alternative hypotheses for a link between stress exposures and components of the innate immune system; 2) examine the association between early stress exposure and adaptive immunity, indexed by T cell responses to latent/persistent virus; and 3) determine the associations between behavioral/emotional and somatic symptoms and immune function in stress-exposed children. We also add a fourth exploratory aim: to examine the links between family and socio-demographic risk and illness and functional outcomes. The proposed study will add significant new information to our understanding of if and how stress exposure is associated with childhood onset dysregulated immune outcomes and the mechanisms involved. Findings from the study will provide a much-needed empirical foundation for developmental and clinical models of the interplay between stress and health in children.

ABSTRACT There is rapidly growing evidence that the health and development of the child and adult can be traced to early environmental influences. However, the vast majority of the evidence is correlational: fundamental questions remain about which specific early exposures confer risk, when in development exposure may have significant and lasting influence, and the mechanisms of effects. This application to the Environmental Influences on Child Health Outcomes (ECHO) RFA (OD-16-004) synthesizes two recently initiated and highly compatible pediatric cohort studies in which environmental exposures are being tracked in 500 pregnant mothers from the 1st trimester; we are already collecting extensive prenatal biological samples and placental samples as well as detailed psychological, socio-demographic, and life history data. We especially target the prenatal period to examine if and how prenatal exposures may ?program? adaptive biological responses in the fetus and child, with carry-forward effects on brain and somatic health; furthermore, we focus particularly on inflammation as a mediator of environmental exposures because it is a compelling biological mechanism by which a wide range of exposures may shape child neurodevelopment and obesity. These data, which cover cellular mechanisms and social demography, will help translate how the range of environmental influences from pregnancy shape child health outcomes. The 500 children will be extensively studied at newborn, 6 months, 1 year, 2 years, 3 years, and 4 years of age using clinically derived and state-of-the-art behavioral, physical and biological assessments of neurodevelopment and obesity. In the UG3 phase we will harmonize protocol development across sites; complete collection of prenatal and a substantial majority of placental samples and perinatal outcomes across cohorts; commence collection of neonatal brain imaging and physical development outcomes. We will also develop models for the biological and social and demographic exposure data in preparation for analyses of child health outcomes in the UH3 phase. For the UH3 phase, we will characterize inflammation from multiple sources throughout pregnancy, in the placenta, and in early infant development to identify its psychosocial, developmental, and environmental exposure origins and sources. In addition, we will test alternative mechanisms by which prenatal exposures and indicators of inflammation predict perinatal outcomes, child obesity, and child neurodevelopment. We will also complete the complex task of biobanking extensive blood, urine, saliva and place samples on approximately 1,000 individuals and contributing the broader ECHO consortium research agenda. The proposed study will add significant new information to our understanding of which environmental influences may have causal influence on child health outcomes, and the timing and mechanisms of these effects. This information will provide a much-needed empirical foundation to know how and when in development to intervene to promote child health outcomes.

Pregnancy marks a period of extreme physiological change as the maternal immune, endocrine, and metabolic systems rapidly adapt to sustain the growing fetus. It is conventionally assumed that these pregnancy-induced changes (e.g., elevated lipids, insulin resistance, weight gain) reverse by 6-months postpartum. Yet, evidence suggests that for some women physiological changes persist and may confer long-term risk of chronic diseases such as cardiovascular disease (CVD). We have demonstrated, for example, that inflammatory markers that confer risk for CVD may stay elevated above pre-pregnancy levels beyond 6-months postpartum. Thus, characterizing weight and biological changes across pregnancy-postpartum, predicting the women at risk for adverse cardiometabolic profiles, and identifying modifiable factors that mitigate these profiles offer opportunities to create targeted interventions to prevent future chronic disease. To improve our understanding of the nature of biological changes in the pregnancy-postpartum period that may predict cardiometabolic risk, we propose a cost-efficient longitudinal study extending from the first trimester through 3 years postpartum that capitalizes on the infrastructure of an ongoing pregnancy cohort (R01 HD083369). The parent study, which focuses on maternal prenatal biology as it relates to child health outcomes, is currently recruiting a socioeconomically and racially diverse sample of 290 first trimester pregnant women. Blood, saliva, anthropometry, and psychosocial, lifestyle, and health data are collected across pregnancy in the parent study. We will leverage the existing infrastructure and data collected as part of the parent study and expand that existing framework by (1) assessing additional biomarkers from banked prenatal maternal samples and obtaining new maternal biological samples at 6, 12, and 36 months postpartum; (2) examining how maternal weight, immune, endocrine, and metabolic biomarkers from the first trimester through 12 months postpartum predict subsequent cardiometabolic risk in the mother, and (3) identifying modifiable maternal health behaviors that may mitigate adverse cardiometabolic health outcomes. Our over-arching premise is that the immune, endocrine, metabolic, and weight changes of pregnancy can be long-lasting and contribute to an adverse cardiometabolic profile that increases long-term chronic disease risk. The aims are to: (1) identify maternal weight profiles in the pregnancy-postpartum period that predict adverse cardiometabolic risk profiles three years postpartum; (2) describe immune, endocrine, and metabolic biomarker profiles in the pregnancy- postpartum period, and determine their associations with cardiometabolic risk; and (3) determine how modifiable health behaviors are associated with weight and biomarker changes in the postpartum period and predict cardiometabolic risk. The significance of this project is high given the increasing rates of obesity in pregnant women and the need for targeted, biologically and psychosocially informed treatments to prevent cardiometabolic disease in women.