Environmental ethoxylated surfactants and metabolic health dysregulation in zebrafish - Project Summary The prevalence of metabolic disorders (e.g., obesity), continues to increase and imposes significant costs on the US health care system. In the US, ~42% of adults (20+ years of age) are classified as obese Exposure to environmental contaminants has been implicated as a causal factor, and some of these contaminants, termed metabolic disrupting chemicals (MDCs), increase weight and lipid accumulation and/or perturb energy balance and/or metabolic homeostasis, contributing to metabolic dysfunction including obesity. Polyethoxylated surfactants (alkylphenols and alcohols) are emerging contaminants with ubiquitous human exposures and robust effects on metabolic health. Used widely in hard surface cleaners, detergents, paints, pesticides, and other products, polyethoxylated surfactants persist in the environment and contribute to chronic human exposure. We have reported an obesogenic effect in zebrafish following developmental exposure to nonylphenol polyethoxylates at environmentally relevant concentrations. In contrast, cetyl alcohol polyethoxylates increased overall adiposity without any apparent impacts on body weights. Given the growing use of these polyethoxylates in consumer products and the lack of comprehensive toxicity assessments on them, it is crucial to determine how polyethoxylates differentially act to disrupt metabolic health. Our central hypothesis is that these polyethoxylates preferentially promote an unhealthy visceral adipose expansion through thyroid hormone receptor antagonism, in part through skewing the commitment of mesenchymal stem cells to the adipose lineage at the expense of osteoblasts. Aim 1 will comprehensively assess the role of thyroid receptor disruption in the observed effects through a combination of in vitro experiments (co-exposures, siRNA knock-down, and chromatin immunoprecipitation with sequencing) and in vivo experiments (co- exposures and genetic knock-down approaches) to rigorously assess the role of thyroid hormone in the observed polyethoxylate-induced metabolic health effects. Aim 2 will directly interrogate the nature of polyethoxylate-induced adiposity via comprehensive assessment of adipose tissue in developmentally exposed zebrafish (histology and adipocyte morphometrics, immune cell infiltration, and metabolomics to measure inflammatory mediators). Paired in vitro experiments will assess impacts on mesenchymal stem cell commitment and differentiation through adipogenesis and osteogenesis assays and single cell transcriptomics to evaluate how polyethoxylates disrupt cell fate and differentiation decisions. This research will move the field forward by supporting a more integrated and physiologically relevant model of contaminant-induced metabolic disease. Given the wide environmental prevalence of polyethoxylates, clear human exposure pathways, and metabolic health impacts in a model with the potential for clear translation to human health, there is a critical need to better characterize effects and their mechanisms. We expect results of our proposed studies will drive additional research into these chemicals, most notably the AEOs that have received limited attention.
