Assessment of Toxicological Perturbations and Variants of Pancreatic Islet Development in the Zebrafish Model.

Karilyn Sant,Haydee Jacobs,Larry Moss,Jennifer Moss,Jiali Xu,Katrina Borofski,Alicia Timme-Laragy

doi:10.3390/toxics4030020

Abstract

The pancreatic islets, largely comprised of insulin-producing beta cells, play a critical role in endocrine signaling and glucose homeostasis. Because they have low levels of antioxidant defenses and a high perfusion rate, the endocrine islets may be a highly susceptible target tissue of chemical exposures. However, this endpoint, as well as the integrity of the surrounding exocrine pancreas, is often overlooked in studies of developmental toxicology. Disruption of development by toxicants can alter cell fate and migration, resulting in structural alterations that are difficult to detect in mammalian embryo systems, but that are easily observed in the zebrafish embryo model (Danio rerio). Using endogenously expressed fluorescent protein markers for developing zebrafish beta cells and exocrine pancreas tissue, we documented differences in islet area and incidence rates of islet morphological variants in zebrafish embryos between 48 and 96 h post fertilization (hpf), raised under control conditions commonly used in embryotoxicity assays. We identified critical windows for chemical exposures during which increased incidences of endocrine pancreas abnormalities were observed following exposure to cyclopamine (2–12 hpf), Mono-2-ethylhexyl phthalate (MEHP) (3–48 hpf), and Perfluorooctanesulfonic acid (PFOS) (3–48 hpf). Both islet area and length of the exocrine pancreas were sensitive to oxidative stress from exposure to the oxidant tert-butyl hydroperoxide during a highly proliferative critical window (72 hpf). Finally, pancreatic dysmorphogenesis following developmental exposures is discussed with respect to human disease.

Highlights

Developmental exposures to environmental toxicants can be highly disruptive to embryonic development, producing outcomes ranging from embryonic lethality and congenital malformations, to subtle physiological or morphological alterations that may predispose individuals to diseases that emerge later in life [1,2,3,4]
Toxics 2016, 4, 20 the lifecourse. This is a fundamental component of the developmental origins of health and disease paradigm, which postulates that later-life effects and chronic diseases such as diabetes could be caused by early-life conditions, including chemical exposures [5]
While Type 1 and Type 2 are distinct diseases with differing causal pathologies, both manifest common aspects of the diabetic phenotype that are related to pancreatic beta cells, elevated blood glucose, largely attributed to insufficient signaling of insulin, and compromised beta cell integrity

Summary

Introduction

Developmental exposures to environmental toxicants can be highly disruptive to embryonic development, producing outcomes ranging from embryonic lethality and congenital malformations, to subtle physiological or morphological alterations that may predispose individuals to diseases that emerge later in life [1,2,3,4]. It is likely that the vast majorities of in utero exposures are less severe and produced by lower-dose exposures of environmental contaminants While these outcomes could manifest pathologically during childhood, these exposures may instead increase fragility of tissues and signaling pathways, and increase susceptibility to future stresses or exposures acquired throughout. Diabetes is a human health problem of increasing concern, with high economic and societal cost [6] Rates of both Type 1 and Type 2 diabetes have increased more than can be predicted by genetics alone, suggesting they may be associated with environmental factors, such as chemical exposures [1,7]. Several environmental toxicants have been associated with the development of diabetes in epidemiological studies, or found to disrupt pancreatic beta cells in animal models. A direct causal link between embryonic exposure and the development of diabetes or metabolic diseases later in life has not yet been firmly established

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