Developmental and behavioral effects of embryonic exposure to the polybrominated diphenylether mixture DE-71 in the killifish (Fundulus heteroclitus)

Exposures to penta polybrominated diphenylether (PeBDE) cause neurobehavioral toxicity in developing mice and rats. As levels of these ubiquitous contaminants are increasing in the environment, this raises concern that wildlife may also suffer such effects, with consequences for their ability to catch prey and avoid predators. PeBDE levels in wild-caught fish have been steadily escalating over the past fifteen years. To our knowledge, behavioral consequences of piscine embryonic exposure to PeBDE has not yet been studied. The objectives of this investigation were to characterize effects on development in an environmentally relevant fish model, and test for latent behavioral effects following cessation of exposure. Embryos from the estuarine minnow, Fundulus heteroclitus, were exposed from day 0-7 post fertilization to the industrial PeBDE mixture, DE-71 (0.001 to 100 microg l(-1)). Embryos were assayed for hatching success, development, and microsomal enzyme cytochrome P4501A (CYP1A) activity, which was determined by analysis of in ovo ethoxy-resorufin-O-deethylase (EROD) activation in embryos. Larval fish were assayed for predation ability, activity level, and fright response to a simulated predator. Juvenile fish were assayed for learning ability in a three-chambered fish maze. No induction of embryonic EROD activity was observed, nor was a high dose of DE-71 able to inhibit EROD activity induced by beta-naphthoflavone. No deformities were detected, but a subtle developmental asymmetry with respect to tail curvature direction was observed, and a hatching delay of up to 4.5 days was noted. Behavioral test results suggest that embryonic exposure to DE-71 may alter activity level, fright response, predation rates, and learning ability in subsequent life stages.     

Fluoranthene, but not benzo[a]pyrene, interacts with hypoxia resulting in pericardial effusion and lordosis in developing zebrafish

Previous research has documented several PAHs that interact synergistically, causing severe teratogenicity in developing fish embryos. The coexposure of CYP1A inhibitors (e.g. FL or ANF) with AHR agonists (e.g. BaP or BNF) results in a synergistic increase in toxicity. As with chemical CYP1A inhibitors, it has also been shown that CYP1A morpholinos exacerbate BNF-induced embryotoxicity. We hypothesized that a hypoxia-induced reduction in CYP1A activity in BNF or BaP-exposed zebrafish embryos would similarly enhance pericardial effusion and other developmental abnormalities. BaP, BNF, ANF, and FL exposures, both individually and as BaP+FL or BNF+ANF combinations, were performed under hypoxia and normoxia. CYP1A activity in the BaP+hypoxia and BNF+hypoxia embryos was reduced by approximately 60% relative to normoxia embryos. Although CYP1A activity was significantly reduced, we did not observe any increase in pericardial effusion in either group. An unexpected yet particularly interesting result of these experiments was the observed interaction of both FL and ANF with hypoxia. Relatively high, yet environmentally relevant concentrations of FL (100-500 microg L(-1)) interact with moderate hypoxia (7.3% DO) through an unknown mechanism, resulting in pericardial effusion and severe lordosis. Additionally, ANF exposures (100 microg L(-1)) which are not normally teratogenic caused dramatic pericardial effusion, but not lordosis, when embryos were coexposed to hypoxia. These results suggest that reduced CYP1A activity may not exclusively underlie observed developmental toxicity, and that hypoxia may exacerbate the developmental toxicity of some PAH mixtures.     

Per- and polyfluoroalkyl substances and obesity,type 2 diabetes and non-alcoholic fatty liver disease: a review of epidemiologic findings

Abstract

Per- and polyfluoroalkyl substances, a group of fluoro-surfactants widely detected in the environment, wildlife, and humans, have been linked to adverse health effects. A growing body of literature has addressed their effects on obesity, diabetes and non-alcoholic fatty liver disease/non-alcoholic steatohepatitis. This review summarizes the brief historical use and chemistry of per- and polyfluoroalkyl substances, routes of human exposure, as well as the epidemiologic evidence for associations between exposure to per- and polyfluoroalkyl substances and the development of obesity, diabetes and non-alcoholic fatty liver disease/non-alcoholic steatohepatitis. We identified 22 studies on obesity and 32 studies on diabetes, while only 1 study was found for non-alcoholic fatty liver disease/non-alcoholic steatohepatitis by searching PubMed for human studies. Approximately two-third of studies reported positive associations between per- and polyfluoroalkyl substances exposure and the prevalence of obesity and/or type 2 diabetes. Causal links between per- and polyfluoroalkyl substances and obesity, diabetes and non-alcoholic fatty liver disease/non-alcoholic steatohepatitis, however, require further large-scale prospective cohort studies combined with mechanistic laboratory studies to better assess these associations.