Environmental Pollutants Disrupting Nuclear Receptor Signaling and Metabolism in Zebrafish

Obesity affects a large proportion of the world’s population, and the alarming rates of increase in its incidence have necessitated several research efforts investigating the risk factors for the disease. Apart from genetic and lifestyle factors, environmental exposure to chemicals, such as the estrogen diethylstilbestrol and the anti-diabetic Thiazolidinediones, are known to induce weight gain in animals and humans. Estrogens and Thiazolidinediones act via the Estrogen Receptors (ERs) and the Peroxisome Proliferator-Activated receptor gamma (PPARγ), respectively. In this study, we identify environmental endocrine disrupting chemicals (EDCs), which may act through ERs or PPARγ, to affect metabolism in zebrafish. Furthermore, we investigate the mechanism by which widely prevalent flame retardants and PPARγ agonists tetrabromobisphenol A (TBBPA) and tetrachlorobisphenol A (TCBPA) induce aberrant lipid accumulation in zebrafish. Through our studies, we have identified 32 environmental chemicals from EPA’s ToxCast library of 309 chemicals as being estrogenic in zebrafish. Through extensive surveys of previously published in vitro and in vivo studies of these chemicals, we infer that in vitro tests for estrogenicity may not fully predict toxicity in vivo, and posit that zebrafish be used in whole-organism high-throughput screens to supplement in vitro chemical prioritization efforts for toxicological testing. We have also established a zebrafish-based quantitative phenotypic screening platform to investigate the effect of environmental chemicals on yolk utilization. Zebrafish utilize the lipid-rich yolk during development, and, we posit that chemical disruption of yolk-lipid utilization could suggest abnormal lipid mobilization and energy demand in developing zebrafish. Using this platform we evaluated nine chemicals, and found that while pesticide prochloraz delays yolk utilization, another pesticide butralin, the mammalian obesogen tributyltin, and TBBPA and TCBPA increase yolk lipid consumption by zebrafish larvae. Transcriptomic analysis of TBBPA, TCBPA and TBT in zebrafish showed that, just as in mammals, these chemicals induce pathways driving adipogenesis. These chemicals also induced the expression of several genes related to lipid metabolism and inflammation. Although further studies are needed to determine the sequence of molecular events triggered by these chemicals, we posit that TBBPA, TCBPA and TBT may act through these pathways to induce obesity in zebrafish, and possibly, in humans.