Environmental Contaminants and Pancreatic Beta-Cells

Abstract

1University of Lille 1, Glycobiology Structural and Functional Unit, Villeneuve D'Ascq, France 2CAPES-Foundation, Ministry of Education Brazil, Brasilia, Brazil3State University of Maringá, Department of Cell Biology and Genetics, Laboratory of Secretion Cell Biology, Maringá, Brazil4UPSP-EGEAL Polytechnic Institute LaSalle de Beauvais, Beauvais, France*in memoriamtermed Langerhans islets, consisting of four different types of endocrine cells known as the beta, delta, alpha, and pancreatic polypeptide (PP) cells which produce, store, and release insulin, glucagon, somatostatin, and pancreatic peptide, respectively. Islets also occur in lower quantities in the acinar structures of the pancreas. Although beta-cells occupy a great part of the volume in the islets, their capacity to proliferate and their neo-formation are extremely reduced compared to other cells (3). Insulin secretion control is distinct from all other cells that release hormones or neurotransmitters; glucose, as a major physiological stimulus, induces very high cellular metabolism activity, promoting the production of adenosine triphosphate (ATP) which can block a specific potassium (K+) channel. Once K+ output is reduced, the beta-cell is depolarized which induces certain calcium (Ca2+) channels to open, permitting a rise in intracellular Ca2+ (1). The cytoskeleton is activated, stimulating the transport of vesicles that contain insulin to the periphery of plasma membrane, where exocytosis is performed and the insulin is released. Save for a few neurons in the hypothalamus, beta-cells can be considered a unique metabolic sensor. Other secretory cells are signalized using mostly a membrane receptor (4). The high incidence of metabolic diseases such as type 2 diabetes cannot be explained solely by the occidental diet and sedentary life style. In the last 10 years, it has been shown that the influence of environmental pollutants such as food contaminants, plasticizers, pesticides (Ps), and organic metallic compounds might contribute to the early onset of obesity and beta-cell malfunction which allows the development of diabetes (5). Environmental contaminants injure pancreatic betacells impairing the metabolism; however, when the exposure is halted, the beta-cells might recover improving the metabolism. Nevertheless, exposure to contaminant during perinatal life can damage the beta-cells disrupting fetal metabolism, a state which can persist even in adulthood (1). There is a theory that certain challenges during gestation, mostly malnourishment, including a restricted caloric diet, that stress the fetus in the maternal womb can compromise growth and development. In this condition, babies are delivered with low birth weight and are at high risk for cardiometabolic disorders such as obesity, hypertension, and diabetes (6). The stressed fetus adopts strategies to maximize its chances for survival and growth in postnatal life. Adapting its metabolism to live in restricted caloric conditions is one such strategy. These survival maneuvers promote the maintenance of noble tissues, such as the brain and heart, but can compromise that of others such as the liver, muscles, and pancreas. However, upon exposure to food abundance, the metabolism saves the excess and overaccumulates energy stocks. This concept, which emerged in the 1990s, is known as developmental origins of health and disease (DOHaD) but also termed the Barker theory, the thrifty phenotype theory, and metabolic programming, among others (7). Interestingly, in the 2000s, a theory that assigns environmental chemicals which affect adults as well as fetuses has emerged. According to this theory, environmental chemicals are the cause of the cardiometabolic disruption pandemic worldwide (8). During gestation, to maintain the development of the fetus, hormone and the hypothalamic-pituitary-thyroid axis (HPA) or even lead to impairment of some TRs and affect thyroid hormone signaling and action (15). Although the EDCs are claimed to elicit obesity by acting directly on white adipose tissue, other structures such as brain, liver, the endocrine pancreas, and especially pancreatic betacells, may be direct targets as well (14). Taken together the abovepresented evidences, the sections of this review aim to show that exposure to any type of EDC may possibly lead to changes in the structure or function of pancreatic beta-cells and play a role in type 2 diabetes onset. Xenoestrogens and EstrogensDuring gestation, regardless of development of GDM, insulin resistance increases due to the requirement of the fetus for glucose (16). The increase of estrogen appears to be linked to insulin secretion and sensitivity as well as to GDM (5). In fact, several studies show that during pregnancy, the pancreatic islets adapt to the high insulin demand. It has been shown that the islets are high in size and number and that proliferation and neogenesis are dramatically increased in beta-cells during this period (17). In the past, this increase was attributed to lactogenic hormones; however, estrogen is currently associated with the increases in insulin secretion and sensitivity. This sexual hormone promotes a protective effect against oxidative stress and pro-inflammatory cytokine-induced apoptosis in pancreatic beta-cells (1).In support of this point, it is known that low levels of estrogen in ovariectomized or aged rats are associated with glucose intolerance, insulin resistance, dyslipidemia, and obesity but, interestingly, it was shown that an excess of estrogen also induced metabolic disruption causing obesity (18). Beta-cells present ERs (ER? and ER?) (1). Indeed, knockout mice to estrogen alphareceptor (ER?KO) exhibit a reduction in glucose transporter type 4 (GLUT4), while knockout mice to estrogen beta-receptor (ER?KO) present no differences although it is well documented that ER? is involved in body fat distribution (5). These observations and comments provide evidence that estrogen can infl