Doctoral Dissertation Research: Intergenerational effects of prenatal stress on physiological and psychosocial outcomes

In recent decades, researchers have underscored the importance of early life experiences, especially those that occur in utero, as factors that shape a variety of human phenotypes across the lifecourse. Growing evidence suggests that some of these early life biological effects can persist into adulthood and, in women of reproductive age, shape the gestational environment experienced by her offspring, thereby influencing grandoffspring development. The hypothalamic-pituitary-adrenal (HPA) axis is a particularly strong candidate pathway for the phenotypic transmission of such multigenerational effects. During pregnancy, maternal stress activates the HPA axis and raises cortisol levels, which can cross the placenta to affect fetal development, including the ontogeny of the HPA axis. Intrauterine stressors, along with postnatal stressors, are believed to have durable effects on HPA function that potentially persist into adulthood. As adults, the alterations in HPA axis regulation are predicted to not only affect susceptibility to stress-influenced disease, particularly poor mental health, but among pregnant females, to also elevate cortisol during pregnancy and program fetal HPA axis development in the grandchildren of the originally exposed grandmother. Past work has consistently shown that maternal prenatal stress predicts early gestational timing and lower birth weight in offspring, who also show evidence for alterations in HPA axis function as infants, consistent with a lasting effect of fetal exposure to maternal cortisol. What is less clear is whether these biological changes persist into adulthood to alter her stress physiology and mental health, and in turn whether the altered regulation of cortisol impacts the gestational environment experienced by grandoffspring. Such effects could allow environments to have multigenerational impacts on biological variation and health, yet to date no study has tested this possibility in humans using prospective, longitudinal data spanning multiple generations. Here we propose to use existing survey data, new data, and sample collection to test the lifecourse and intergenerational effects of early life stress experienced by now young-adult mothers who, as black South Africans, were exposed to discrimination, stress and political upheaval at the end of the apartheid era in Soweto, South Africa. We avail of the longitudinal “Birth to 20” study that first enrolled pregnant women in 1990 and has since followed their children and grandchildren for 28 years. This study provides a unique opportunity to trace the long-term impacts of early life stress exposure, focusing on both the adult health of the exposed, and the birth outcomes and HPA function of their unexposed offspring.