Files
Abstract
Per- and Polyfluoroalkyl Substances (PFAS) are a diverse class of industrial chemicals that have been utilized for decades in various applications due to their unique water- and grease-resistant properties. These substances have become ubiquitous in the environment, primarily as a result of widespread use in consumer products, food packaging, and industrial processes. Their persistence in the environment and bioaccumulation in living organisms has raised significant concerns regarding human health and ecological impacts, particularly as PFAS have been consistently detected in human bloodstreams, indicating a direct link between environmental exposure and potential health risks. Numerous studies have associated PFAS exposure with a range of adverse health outcomes, including hepatotoxicity, immunotoxicity, endocrine disruption, tumorigenicity, and neurotoxicity. Developmental neurotoxicity (DNT) has garnered particular attention due to the alarming increase in neurodevelopmental disorders observed in children linked to both pre- and postnatal exposure to PFAS. The growing prevalence of conditions such as attention deficit hyperactivity disorder (ADHD), autism spectrum disorders, and learning disabilities in children raises critical questions about the long-term impacts of PFAS on neurodevelopment. In this dissertation, we aimed to develop a quantitative adverse outcome pathway (qAOP) network for assessing the developmental neurotoxicity (DNT) of PFAS mixtures using the model organism Caenorhabditis elegans. To explore these pathways, we employed the nematode Caenorhabditis elegans as a model organism, which is particularly well-suited for neurotoxicologically studies due to its simplicity, possessing only 302 neurons and a fully mapped network of chemical and electrical connections, enabling detailed examination of neurotoxic effects while facilitating high-throughput screening (HTS) for assessing cognitive impairments. The qAOP framework elucidates how PFAS exposure initiates neurodevelopmental disruptions through a sequence of biologically relevant key events (KEs). The qAOP integrates findings from C. elegans model systems, highlighting critical exposure windows and the impact of PFAS mixtures on neurodevelopment. By systematically linking these KEs and KERs, this framework advances the understanding of PFAS-induced neurotoxicity and supports more informed risk assessments. The dynamic nature of the qAOP framework ensures it can accommodate new scientific data and advancements, enhancing its applicability for regulatory science and public health protection.