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Poly- and perfluoroalkyl substances (PFAS) are a class of bioaccumulative toxicants used in numerous industrial and commercial products. Perfluorooctanesulfonic acid (PFOS) alters pancreatic organogenesis during development, and perfluorohexanesulfonic acid (PFHxS) has been suggested as a replacement for PFOS due to its shorter carbon chain, but they are often found together in surfactants, such as legacy aqueous film-forming foam. This study investigates how developmental exposures to a PFAS mixture (PFHxS + PFOS) impact the developing exocrine pancreas. Zebrafish embryos (Tg(ptf1a:GFP)) were exposed to 0.01% DMSO, or 8, 16, 32 μM PFHxS alone, 16 μM PFOS alone, and 8, 16, and 32 μM PFHxS plus 16 μM PFOS. Embryos underwent refreshing exposures (3 hours post fertilization (hpf) - 96 hpf) or static exposures (3, 24, 48, or 72 hpf - 96 hpf) and then live imaging to quantify the truncated exocrine pancreas phenotype that occurred, and at what point in development it became apparent. PFAS mixtures significantly impacted growth parameters and exocrine pancreas length. The truncated pancreas phenotype was seen most often in the 16 μM PFHxS + 16 μM PFOS treatment group, so this concentration was used for subsequent experiments. Time lapse imaging (58 - 72 hpf, 80 - 96 hpf) and cellular proliferation assays (3 - 96 hpf) were used to ascertain the cause of the truncated phenotype as an issue of cellular migration or proliferation within the pancreas. Cell migration and proliferation were decreased in response to toxicant exposure. This study offers insights to how developmental exposures to toxicants may impact the pancreas.

Indiana University-Purdue University Indianapolis (IUPUI) / Traditionally, the exocrine and endocrine cellular compartments of the pancreas have been considered distinct functional systems. However, recent studies suggest a more intricate relationship between the exocrine and endocrine, which may impact pancreatic growth and health. Additionally, translational control mechanisms have been linked to organ development. Our lab has shown that the mRNA translation factor eukaryotic initiation factor 5A (eIF5A), when in its post-translationally modified “hypusinated” form, plays a role in pancreas development. The hypusination of eIF5A requires the rate-limiting enzyme deoxyhypusine synthase (Dhps) to post- translationally modify a critical lysine residue which in turn produces the active form of eIF5A that functions in mRNA translation. When we generated animals with a deletion of Dhps in the pancreatic progenitor cells, there was no alteration in islet mass but significant exocrine insufficiency at embryonic (E) day 18.5 concomitant with downregulation of proteins required for exocrine pancreas development and function. Resultantly these animals died by 6 weeks-of-age. These observations prompted the question, is the phenotype caused by the absence of hypusinated eIF5A or the increase of unhypusinated eIF5A? To address this, we generated a mouse model wherein Eif5a is deleted in the pancreas (eIF5A∆PANC) and these mutant animals also display exocrine insufficiency. Interestingly, beta cell mass is increased at E18.5, and the mutant animals maintain euglycemia and survive up to 2 years. Ongoing analyses are interrogating the differences between these animal models with the goal to determine if mRNA translation facilitates cellular communication between the exocrine and endocrine pancreas.

The proposal of this work was to determine the contribution of functional MR imaging techniques, i.e. secretin-enhanced MRCP (S-MRCP) and dynamic contrast-enhanced magnetic resonance (DCE-MR) imaging in the quantitative assessment of exocrine pancreatic function and perfusion.<p><p>The pancreas is both an exocrine and endocrine organ, though the exocrine tissue accounts for more than 90%. The exocrine pancreas is specialized in the synthesis and storage of digestive enzymes and in bicarbonate and water secretion in response respectively to various secretagogues (CCK, ach, GRP, VIP,…) and to secretin. <p>The arterial supply of the pancreas derives from branches of the celiac trunk and of the superior mesenteric artery. The microvascularity of the exocrine and the endocrine parts of the gland are anatomically and functionally separated, with differentially regulated blood perfusion. <p>Based on the knowledge of a close relationship between the activity of the gland and its blood supply, in normal conditions pancreatic perfusion responds to the functional state of the exocrine parenchyma: increased demands for exocrine secretions are associated with increased pancreatic blood flow. <p>The pancreatic gland can be involved at different degrees of severity in acute and chronic inflammatory processes due to various causes. In both processes microcirculatory changes occur and the pancreatic exocrine function can be impaired. Moreover, an exiguous microvascular component characterizes pancreatic ductal adenocarcinoma (PDA) related to a prominent stroma.<p><p><p>In the first section of this thesis, quantitative assessment of the pancreatic exocrine secretions was performed with S-MRCP in physiologic and non-physiologic conditions. The stimulating effect of secretin as well as the inhibitory effect of somatostatin on normal pancreas, both administered at different dose-regimens, were tested. The results of these investigations showed that quantitative S-MRCP is able to detect changes in pancreatic exocrine secretions correlated to the degree of stimulation or inhibition. <p>In pathologic settings, pancreatic exocrine secretions were assessed in chronic pancreatitis patients showing different degrees of severity, before and after endoscopic pancreatic duct drainage procedures (PDDP). In the group of patients presenting a reduced pancreatic exocrine reserve before treatment, quantitative S-MRCP showed a short-term improvement after PDDP. <p><p>In the second section, the feasibility and the reproducibility of DCE-MR imaging to quantify regional pancreatic perfusion was firstly investigated. DCE-MR imaging was performed in normal volunteers. Reference values for regional pancreatic perfusion were achieved with an intra-individual variability of 21%.<p>DCE-MR investigations were repeated during secretin stimulation and disclosed a significant increase of regional pancreatic perfusion in all individuals. <p>Secondly, DCE-MR imaging investigated benign and malignant focal pancreatic solid lesions and non tumoral tissue in patients undergoing pancreatic surgical resection. The purpose was to correlate DCE-MR quantitative parameters, (reflecting perfusion and/or permeability and the distribution volume fraction) with histologic features such as the degree of fibrosis and the microvascular density (MVD) in the corresponding tissues. A significant correlation was found between DCE-MR and histologic parameters: Ktrans was negatively correlated with the degree of fibrosis (high fibrosis was correlated with low perfusion), while the distribution volume fraction was positively correlated with the degree of fibrosis and with MVD (larger EES was correlated with high fibrosis and higher MVD). <p> / Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished

<p>  </p> <p>Traditionally, the exocrine and endocrine cellular compartments of the pancreas have been considered distinct functional systems. However, recent studies suggest a more intricate relationship between the exocrine and endocrine, which may impact pancreatic growth and health. Additionally, translational control mechanisms have been linked to organ development. Our lab has shown that the mRNA translation factor eukaryotic initiation factor 5A (eIF5A), when in its post-translationally modified “hypusinated” form, plays a role in pancreas development. The hypusination of eIF5A requires the rate-limiting enzyme deoxyhypusine synthase (<em>Dhps</em>) to post-translationally modify a critical lysine residue which in turn produces the active form of eIF5A that functions in mRNA translation. When we generated animals with a deletion of <em>Dhps</em> in the pancreatic progenitor cells, there was no alteration in islet mass but significant exocrine insufficiency at embryonic (E) day 18.5 concomitant with downregulation of proteins required for exocrine pancreas development and function. Resultantly these animals died by 6 weeks-of-age. These observations prompted the question, is the phenotype caused by the absence of hypusinated eIF5A or the increase of unhypusinated eIF5A? To address this, we generated a mouse model wherein <em>Eif5a</em> is deleted in the pancreas (eIF5A∆PANC) and these mutant animals also display exocrine insufficiency. Interestingly, beta cell mass is increased at E18.5, and the mutant animals maintain euglycemia and survive up to 2 years. Ongoing analyses are interrogating the differences between these animal models with the goal to determine if mRNA translation facilitates cellular communication between the exocrine and endocrine pancreas.</p>

Le diabète de type 1 (DT1) est une maladie auto-immune caractérisée par la destruction des cellules β pancréatiques par les cellules immunitaires, ce qui entraîne une insuffisance en insuline. L’étude des souris Non-Obese Diabetic (NOD), qui développent spontanément le diabète auto-immun, a permis l'identification de plusieurs loci de susceptibilité associés au diabète, appelés Idds. D’ailleurs, Idd1 est lié au locus du CMH. L’utilisation de souris congéniques NOD.B6-Idd1 et B6.NOD-Idd1 a démontré qu’Idd1 est nécessaire mais insuffisant pour la progression du diabète auto-immun. Précédemment, nous avons démontré que les allèles de résistance au locus Idd2 offrent une protection significative contre l’apparition du diabète auto-immun, semblable à Idd1. Pour identifier les facteurs génétiques minimaux requis pour l'apparition du DT1, nous avons introduit les loci NOD Idd1 et Idd2 chez des souris B6, générant des souris doubles congéniques B6.Idd1.Idd2. Bien que la combinaison de Idd1 et Idd2 n’est pas suffisante pour induire l’apparition du diabète, nous avons observé une infiltration immunitaire dans le pancréas exocrine des souches congéniques B6 Idd2. De plus, nous avons observé d'importantes différences phénotypiques dans les sous-populations de lymphocytes T chez les souris B6.Idd1.Idd2 par rapport aux souris simple congéniques, suggérant une interaction épistatique entre Idd1 et Idd2 dans la modulation des fonctions des lymphocytes T. De plus, des augmentations de neutrophiles et de la fibrose spécifiques à Idd2 ont été découvertes, suggérant qu’Idd2 est impliqué dans le processus cellulaire inflammatoire du diabète auto-immun. Dans l’ensemble, ces données montrent que la combinaison des allèles de susceptibilité Idd1 et Idd2 ne mène pas à la progression du diabète auto-immun. Des facteurs génétiques ou environnementaux supplémentaires sont donc nécessaires pour provoquer le diabète auto-immun chez la souris. Néanmoins, nous constatons que les allèles NOD au niveau des locus Idd2 coopèrent pour induire une inflammation et une infiltration immunitaire dans le pancréas. / Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of pancreatic β cells by immune cells, leading to an insulin deficiency. Non-Obese Diabetic (NOD) mice, which spontaneously develop autoimmune diabetes, have enabled the identification of several loci associated with diabetes susceptibility, termed Idds. Notably, Idd1 is linked to the MHC locus and resistance alleles at this locus provide full protection from diabetes onset. Conversely, C57BL/6 (B6) mice bearing NOD Idd1 alleles exhibit immune infiltration in the pancreas without causing overt diabetes. These results show that NOD Idd1 alleles are necessary but not sufficient for autoimmune diabetes progression. In a previous study, we demonstrated that diabetes resistance alleles at the Idd2 locus provide significant protection from autoimmune diabetes onset, second to Idd1. To identify the minimal genetic factors required for T1D onset, we introduced the NOD Idd1 and Idd2 loci in B6 mice, generating B6.Idd1.Idd2 double congenic mice. Although the introduction of susceptibility alleles at both Idd1 and Idd2 was not sufficient to induce diabetes onset, we observed immune infiltration in the exocrine pancreas of B6 Idd2 congenic strains. In addition, we observed important phenotypic differences in T cell subsets in B6.Idd1.Idd2 mice relative to single congenic mice, suggesting epistatic interaction between Idd1 and Idd2 in modulating T cell functions. Moreover, Idd2-specific increases in neutrophils and fibrosis were discovered, suggesting that Idd2 is involved in the inflammatory cellular process of autoimmune diabetes. Altogether, these data show that susceptibility alleles at Idd1 and Idd2 together are not sufficient to autoimmune diabetes progression. Additional genetic factors or environmental triggers are therefore required to cause autoimmune diabetes in mice. Still, we find that NOD alleles at the Idd2 loci cooperate to induce inflammation and immune infiltration in the pancreas.