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BEDREHELSE-Bedre helse og livskvalitet

Transmaternal exposure to bisphenol A and phthalates and the development of type 1 diabetes

Awarded: NOK 3.4 mill.

I have exposed mice (NOD mice), that spontaneously develop autoimmune diabetes type 1 (T1DM) to bisphenol A (BPA) and to a mixture of phthalates, mimicking human mixed exposure. Our results indicate that BPA, but not phthalates have negative effects in the pancreas (reduced macrophage function and number in pancreas and increased number of apoptotic cells in pancreas) and increases the diabetes development in these mice. Phthalates alone do not show the same effect and diminish some of the effects of BPA in the mixture- exposure but increases the systemic effects of BPA, like cytokine secretion and inflammation in pancreas. An explanation for mixes having different effects than single chemicals could be that a mixture with a high total concentration of estrogen like substanses could alter hormone levels, insulin secretion or beta-cell survival. We have shown that BPA reduces macrophage function (phagocytosis) in in vitro studies of peritoneal macrophages from both NODmice, wild type mice and rats from both sexes and different age stages (adult and newly born). One of the most important macrophage functions is to clear apoptotic cells from the pancreas to avoid inflammation signalling to the immune system. Increased inflammation in the pancreas, severe insulitis, causes autoimmune degradation of insulin producing beta-cells and is the initiation of diabetes development. We have also seen a similar, but weaker effect of BPA on human isolated macrophages in vitro. The reason for a weaker effect might be that the cells isolated from human peripheral blood are monocytes that have to be differentiated into macrophages in vitro and these are not equal to the already mature macrophages in the peritoneum. To compare the methological difference between rodent and human macrophages we have isolated rat monocytes from blood with an in vitro differentiation to macrophages and found that these cells are as sensitive to environmental chemicals as the human cells. Our data shows that macrophages isolated from the peritoneum are more sensitive to environmental chemicals than peripheral differentiated blood cells in rat, which possibly could be similar in humans. We have also seen that not only BPA but also perfluorinated compunds (PFUnDA and PFDA) could have negative effects on macrophage phagocytosis in vitro. We have also analysed cytotoxicicyt induced by these chemicals, and found an incerased cytotoxicity at the highest doses. This could explain the decreased macrophage function due to the exposure and also cause increased apoptosis singaling in the pancreas leading to accelerated insulitis development.

The Scandinavian countries have the highest prevalence of type 1 diabetes in the world with a steady increase in Norway of 600 new cases yearly. Type 1 diabetes mellitus (T1DM) is an autoimmune insulin-deficiency due to destruction of insulin-producing be ta-cells. It is the most common type of diabetes in children and is induced by various environmental factors acting on a genetic predisposition. There is a parallel occurrence of increased diabetes prevalence and a high exposure burden of endocrine disrup tors (EDs), leaking from consumer products, over the last decades. Continous presence of these chemicals in urine from adults, children and even infants reflects a constant exposure to EDs. The aim of the proposed project is to investigate the effect of EDs on the development of T1DM. We will investigate the effect of combined exposure to some of the most commonly found EDs, bisphenol A, di(2-ethylhexyl) phthalate (DEHP), diisobuthyl phthalate (DIBP), dibuthyl phthalate (DBP) and benzyl buthyl phthalate (BBP), in a mouse model for T1DM. Non obese diabetic (NOD) mice spontaneously develop T1DM and we will monitor if the selected endocrine disruptors have an impact on the time of onset and insidence of the disease. To enable fetal and early life exposure w e will expose pregnant and lactating mice. Progression of T1DM in pups will be monitored through measurements of blood glucose, autoantibodies, proinflammatory cytokines and immuno-phenotyping of peripheral lymph nodes. The degree of insulitis in the panc reas and the amount of apoptotic beta cells will be evaluated. Furthermore, the mechanisms involved in beta-cell death will be investigated ex vivo in pancreatic islets and in a beta cell-line in vitro. The knowledge gained in this project will help to improve toxicological evaluations and health hazard assessment of EDs since there is limited knowledge on immunological effects of transmaternal exposure to a combination of these chemicals.

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BEDREHELSE-Bedre helse og livskvalitet