Uncovering Temporal Windows of Susceptibility: The Role of Temperature in Shaping Birthweight and Epigenetic Patterns During Pregnancy

Abstract

AbstractThe health and well-being of the next generation begin long before birth. Increasingly, research has highlighted the prenatal period as a critical window when the developing fetus is especially sensitive to environmental influences. Exposures during this delicate stage can shape not only immediate birth outcomes but also long-term health trajectories into childhood and adulthood. This dissertation investigates the effect of ambient temperature during pregnancy on potential impacts on birth outcomes and early-life epigenetic changes. By integrating birth outcome analysis with epigenetic insights, this work aims to contribute to a broader understanding of how environmental conditions during pregnancy may shape both immediate and lifelong health. Mother-infant dyads were enrolled from university-affiliated obstetric clinics between April 2018 and March 2020 as part of the Stress and Health in Pregnancy (SHIP) cohort based at North Carolina State University in Raleigh, North Carolina. Women were eligible if they were 18 years or older, spoke English or Spanish and planned to deliver at the study-affiliated hospital. Women were excluded from the study if the fetus had any known congenital anomalies or chromosomal disorders, or if the mother was diagnosed with HIV, Hepatitis C, or Hepatitis B. After enrollment, women completed questionnaires covering demographics, health behaviors, and provided obstetric, medical, and social histories. Maternal obstetric and infant delivery records were abstracted post-delivery. Daily temperature exposure was estimated using the Daymet dataset, which provides high-resolution, gridded climate data across North America at a spatial resolution of 1 km x 1 km. Maximum daily temperatures were assigned to participants based on geocoded residential addresses. The maximum daily temperature values were averaged to create weekly exposure estimates. The second Chapter showed that 1°C rise in temperature during gestational weeks 36 to 40 corresponded to a modest increase in birth weight, with a stronger effect observed in male infants during weeks 35 to 40. Earlier pregnancy exposure (weeks 8 to 17) was also linked to increased birth weight in males. Notably, among infants born to mothers with pre-pregnancy diabetes, the association was substantially greater, with late pregnancy temperature increases associated with a pronounced rise in birth weight. These findings suggest that fetal growth responses to ambient temperature may vary based on the biological sex of the infant and maternal health status, highlighting the need for further research into the underlying biological mechanisms and potential clinical implications. The third chapter identified 1,291 CpG sites with significant associations between prenatal temperature exposure and DNA methylation at birth. Among the top-ranked sites, several mapped to genes involved in neurodevelopment (SHANK2), immune function (RFTN1), and placental adhesion (ITGA6), with varying windows of sensitivity across gestation. These findings underscore the importance of temporally resolved modeling in uncovering critical periods of vulnerability. In the fouth chapter the pathway enrichment analyses (FGSEA and FORA) identified 24 intersecting KEGG pathways enriched for genes linked to CpG sites with high predictive power (normalized MSE < 0.5). These pathways encompassed cardiomyopathy-related mechanisms, neurodevelopmental processes, endocrine signaling, and stress response regulation. Notably, AKT1, AKT3, and PAK1 emerged as key genes with potential relevance for developmental programming. These results suggest that prenatal temperature exposure may have lasting effects on child health by modulating epigenetic marks in genes involved in critical developmental processes. The observed enrichment of cardiomyopathy and neurodevelopmental pathways underscores the need for early-life environmental protections, particularly as climate-related temperature extremes become more frequent. The Chapters highlights the critical role of environmental exposures during pregnancy in shaping infant health outcomes. By leveraging high-resolution temperature data and advanced statistical methods, we observed significant associations between prenatal temperature exposure and key birth outcomes. These findings underscore the importance of studying environmental influences during this sensitive developmental window, as exposure to extreme temperatures may have lasting effects on fetal growth trajectories and overall health. Given these implications, there is a pressing need for public health strategies aimed at mitigating the impact of extreme temperature events. Policies that promote access to cooling resources, improve housing conditions, and support maternal adaptation to climate-related stressors could help protect vulnerable populations and promote healthier birth outcomes.