| 1. |
- Alavian-Ghavanini, Ali, et al.
(författare)
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Prenatal Bisphenol A Exposure is Linked to Epigenetic Changes in Glutamate Receptor Subunit Gene Grin2b in Female Rats and Humans
- 2018
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Bisphenol A (BPA) exposure has been linked to neurodevelopmental disorders and to effects on epigenetic regulation, such as DNA methylation, at genes involved in brain function. High doses of BPA have been shown to change expression and regulation of one such gene, Grin2b, in mice. Yet, if such changes occur at relevant doses in animals and humans has not been addressed. We investigated if low-dose developmental BPA exposure affects DNA methylation and expression of Grin2b in brains of adult rats. Furthermore, we assessed associations between prenatal BPA exposure and Grin2b methylation in 7-year old children. We found that Grin2b mRNA expression was increased and DNA methylation decreased in female, but not in male rats. In humans, prenatal BPA exposure was associated with increased methylation levels in girls. Additionally, Iow APGAR scores, a predictor for increased risk for neurodevelopmental diseases, were associated with higher Grin2b methylation levels in girls. Thus, we could link developmental BPA exposure and Iow APGAR scores to changes in the epigenetic regulation of Grin2b, a gene important for neuronal function, in a sexual dimorphic fashion. Discrepancies in exact locations and directions of the DNA methylation change might reflect differences between species, analysed tissues, exposure level and/or timing.
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| 2. |
- Dunder, Linda, et al.
(författare)
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Low-dose developmental bisphenol A exposure alters fatty acid metabolism in Fischer 344 rat offspring
- 2018
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Ingår i: Environmental Research. - : Elsevier. - 0013-9351 .- 1096-0953. ; 166, s. 117-129
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Tidskriftsartikel (refereegranskat)abstract
- Background. Bisphenol A (BPA) is an endocrine disruptor and also a suggested obesogen and metabolism-disrupting chemical. Accumulating data indicates that the fatty acid (FA) profile and their ratios in plasma and other metabolic tissues are associated with metabolic disorders. Stearoyl-CoA desaturase 1 (SCD-1) is a key regulator of lipid metabolism and its activity can be estimated by dividing the FA product by its precursor measured in blood or other tissues. Objective: The primary aim of this study was to investigate the effect of low-dose developmental BPA exposure on tissue-specific FA composition including estimated SCD-1 activity, studied in 5- and 52-week (wk)-old Fischer 344 (F344) rat offspring. Methods: Pregnant F344 rats were exposed to BPA via their drinking water corresponding to 0: [CTRL], 0.5: [BPA0.5], or 50 mu g/kg BW/day: [BPA50], from gestational day 3.5 until postnatal day 22. Results: BPA0.5 increased SCD-16 (estimated as the 16:1n-7/16:0 ratio) and SCD-18 (estimated as the 18:1n-9/ 18:0 ratio) indices in inguinal white adipose tissue triglycerides (iWAT-TG) and in plasma cholesterol esters (PL-CE), respectively, in 5-wk-old male offspring. In addition, BPA0.5 altered the FA composition in male offspring, e.g. by decreasing levels of the essential polyunsaturated FA linoleic acid (18:2n-6) in iWAT-and liver-TG. No differences were observed regarding the studied FAs in 52-wk-old offspring, although a slightly increased BW was observed in 52-wk-old female offspring. Conclusions: Low-dose developmental BPA exposure increased SCD-16 in iWAT-TG and SCD-18 in PL-CE of male offspring, which may reflect higher SCD-1 activity in these tissues. Altered desaturation activity and signs of altered FA composition are novel findings that may indicate insulin resistance in the rat offspring. These aforementioned results, together with the observed increased BW, adds to previously published data demonstrating that BPA can act as a metabolism disrupting chemical.
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| 3. |
- Dunder, Linda, et al.
(författare)
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Urinary bisphenol A and serum lipids : a meta-analysis of six NHANES examination cycles (2003-2014)
- 2019
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Ingår i: Journal of Epidemiology and Community Health. - : BMJ PUBLISHING GROUP. - 0143-005X .- 1470-2738. ; 73:11, s. 1012-1019
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Tidskriftsartikel (refereegranskat)abstract
- Background: Mounting evidence from both experimental and epidemiological studies suggest that exposure to the endocrine disruptor bisphenol A (BPA) has a role in metabolic disorders. The aim of the present study was to assess whether urinary BPA concentrations were associated with dyslipidaemia in children (<= 17 years old) and adults (>= 18 years old) by performing a meta-analysis of data from six cycles (2003-2014) in the National Health and Nutrition Examination Survey (NHANES).Methods: We conducted a meta-analysis of data from 4604 children and 10 989 adult participants who were part of a substudy of urinary BPA measurements from six NHANES cycles from 2003 to 2014. Linear regression models conducted in each cycle were used to perform a meta-analysis to investigate associations between urinary BPA and serum levels of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), triglycerides (TG) and apolipoprotein B (ApoB).Results: The meta-analysis did not disclose any significant associations between urinary BPA concentrations and LDL-C, HDL-C, TC, TG and ApoB in children. In adults, the meta-analysis revealed negative regression coefficients for all five lipid variables. However, no associations were significant following Bonferroni correction for multiple tests.Conclusions: In the present meta-analysis of cross-sectional data from NHANES, no associations were found between urinary BPA and the five different lipid variables when investigated in both children and adults. However, considering the cross-sectional nature of the present study, results should be clarified in carefully designed longitudinal cohort studies with repeated BPA measurements.
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| 4. |
- Ekeblad, Sara, et al.
(författare)
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Co-expression of ghrelin and its receptor in pancreatic endocrine tumours
- 2007
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Ingår i: Clinical Endocrinology. - : Wiley. - 0300-0664 .- 1365-2265. ; 66:1, s. 115-122
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Tidskriftsartikel (refereegranskat)abstract
- Objective Expression of ghrelin has been reported in pancreatic endocrine tumours, but data on ghrelin receptor protein expression are lacking. The aim of this study was to examine the ghrelin receptor, as well as ghrelin, in a selected series of these tumours, including multiple endocrine neoplasia 1 (MEN1) associated tumours, and to correlate data with clinical features including body mass index.Design Immunohistochemical detection of ghrelin and its receptor was performed on frozen tissue from 31 tumours: 9 MEN1 and 22 sporadic. Twenty tumours were analysed by quantitative PCR. Plasma ghrelin was assessed in 26 patients.Results Twenty-one (68%) of 31 tumours showed immunoreactivity for ghrelin (8/9 MEN1) and 19/20 expressed ghrelin mRNA. Ghrelin receptor protein was detected in 21/30 (70%) tumours (4/8 MEN1), and mRNA was detected in all analysed tumours. Insulinomas had significantly higher levels of receptor mRNA than other tumours. Five patients had elevated plasma ghrelin (> 2 SD above the control group mean). No significant difference in mean plasma ghrelin levels was found between patients (908 ± 569 ng/l) and controls (952 ± 164 ng/l). Mean BMI was 24·3 kg/m2. There was no association between ghrelin or receptor expression and survival.Conclusions We report the first immunohistochemical data on expression of the ghrelin receptor in pancreatic endocrine tumours: 70% of tumours in our material. Concomitant ghrelin and receptor expression was seen in 50% of tumours, indicating an autocrine loop. Ghrelin was expressed in 68% of tumours (8/9 MEN1). Despite frequent ghrelin expression, elevated circulating ghrelin is rare in these patients.
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| 5. |
- Ekeblad, Sara, et al.
(författare)
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Gastrointestinal stromal tumors express the orexigen ghrelin
- 2006
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Ingår i: Endocrine-related cancer. - : Bioscientifica. - 1351-0088 .- 1479-6821. ; 13:3, s. 963-70
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Tidskriftsartikel (refereegranskat)abstract
- Expression of the neuroendocrine marker synaptic vesicle protein 2 (SV2) has been reported in a few cases of gastrointestinal stromal tumors (GISTs). The goal of the present study was to assess the relevance of this finding and identify a possible hormone production in these tumors. We chose to study the orexigen ghrelin and its receptor, since these patients are seldom cachexic, even in advanced disease stages. We investigated ghrelin expression by means of immunohistochemistry on frozen or paraffin-embedded sections from 22 GISTs from a well-characterized patient material. Expression of the growth hormone secretagogue receptor, the ghrelin receptor, was investigated in a subset of lesions. In six tumors, mRNA levels of ghrelin, the ghrelin receptor, and SV2 were analyzed by real-time quantitative PCR. Totally 17 out of 22 tumors showed immunoreactivity for ghrelin. Five out of ten tumors were immunoreactive for the ghrelin receptor, and all of these co-expressed ghrelin. All tumors expressed ghrelin, ghrelin receptor, and SV2 mRNA. GISTs frequently express SV2, ghrelin, and its receptor, indicating the presence of autocrine/paracrine loops.
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| 6. |
- Ekeblad, Sara, et al.
(författare)
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Prognostic Relevance of Survivin in Pancreatic Endocrine Tumors
- 2012
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Ingår i: World Journal of Surgery. - : Springer Science and Business Media LLC. - 0364-2313 .- 1432-2323. ; 36:6, s. 1411-1418
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Better prognostic markers are needed for pancreatic endocrine tumors. Survivin is an apoptosis inhibitor that is suggested to have a negative prognostic impact in several tumor types. Contradictory data exist, especially regarding the significance of a nuclear versus cytoplasmic location of survivin. The prognostic relevance of nuclear and cytoplasmic survivin expression in pancreatic endocrine tumors-controlled for the tumor Ki-67 index, World Health Organization classification, and TNM stage-was investigated. METHODS: A total of 111 patients treated at a tertiary referral center were retrospectively evaluated. Clinical data were gathered from medical records. Immunohistochemistry for survivin and Ki-67 was performed on paraffin-embedded tissue. Univariate and multivariate Cox analyses were performed. RESULTS: Patients with tumors that had <5% survivin-positive nuclei had a mean survival of 225 months [95% confidence interval (CI) 168-281]. The corresponding figure for patients with 5 to 50% survivin-positive tumor cell nuclei was 101 months [95% CI 61-140; hazard ratio (HR) 2.4; P < 0.01) and with >50% survivin-positive nuclei 47 months (95% CI 24-71; HR 4.9; P < 0.001). Nuclear survivin expression in >50% of the tumor cells was an independent marker of a poor prognosis (HR 5.7; P < 0.01). Cytoplasmic survivin was not a significant prognostic factor in the multivariate analysis (HR 0.94; P = 0.90). CONCLUSIONS: High expression of nuclear survivin is a significant marker of a poor prognosis in patients with a pancreatic endocrine tumor.
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| 7. |
- Fjallskog, Marie-Louise, et al.
(författare)
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Expression of molecular targets for tyrosine kinase receptor antagonistsin malignant endocrine pancreatic tumors
- 2003
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 9:4, s. 1469-1473
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Molecular targeting with monoclonal antibodies and tyrosine kinase inhibitors is a novel approach to cancer treatment. We have examined the expression of molecular targets in patients with malignant endocrine pancreatic tumors, which is necessary to justify additional studies investigating the potential benefit from such treatment. EXPERIMENTAL DESIGN: Thirty-eight tumor tissues from malignant endocrine pancreatic tumors were examined with immunohistochemistry using specific polyclonal antibodies with regard to the expression pattern of platelet-derived growth factor receptors (PDGFRs) alpha and beta, c-kit, and epidermal growth factor receptor (EGFR). RESULTS: All 38 tissue specimens expressed PDGFRalpha on tumor cells, and 21 of 37 specimens (57%) expressed PDGFRalpha in tumor stroma (1 specimen was nonevaluable). Twenty-eight samples (74%) stained positive for PDGFRbeta on tumor cells, and 36 of 37 samples (97%) stained positive for PDGFRbeta in the stroma (1 specimen was nonevaluable). Thirty-five tumor tissues (92%) stained positive for c-kit, and 21 (55%) stained positive for EGFR on tumor cells. No differences were seen between syndromes or between poorly differentiated or well-differentiated tumors. Previous treatment did not influence expression pattern. Receptor expression pattern varied considerably between individuals. CONCLUSIONS: We have found that tyrosine kinase receptors PDGFRs alpha and beta, EGFR, and c-kit are expressed in more than half of the patients with endocrine pancreatic tumors. Because these receptors represent molecular targets for STI571 and ZD1839 (tyrosine kinase inhibitors) and IMC-C225 (a monoclonal antibody), we propose that patients suffering from EPTs might benefit from this new treatment strategy. However, because of great variability in receptor expression pattern, all patients' individual receptor expression should be examined.
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| 8. |
- Johansson, T, et al.
(författare)
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Lack of Nuclear Expression of Hairy and Enhancer of Split-1 (HES1) in Pancreatic Endocrine Tumors
- 2008
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Ingår i: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 0018-5043 .- 1439-4286. ; 40:5, s. 354-359
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Tidskriftsartikel (refereegranskat)abstract
- The Notch signaling cascade plays a vital role in the proliferation and differentiation of cells during pancreatic development. Cell line experiments have suggested the involvement of Notch signaling in pancreatic endocrine tumorigenesis. We investigated the expression of NOTCH1, HES1, HEY1 and ASCL1 in pancreatic endocrine tumors and compared the data to tumor phenotype including hormone production, heredity, and WHO classification. Real-time quantitative PCR and immunohistochemistry were performed on samples of 26 pancreatic endocrine tumors. For comparison, 10 specimens of macroscopically normal pancreas were analyzed using immunohistochemistry. The subcellular localization of proteins was determined. Neither hormone production, nor heredity, or WHO classification was found to be associated with the expression of these proteins. There were discrepancies between mRNA and protein expression levels. All tumors displayed ASCL1 immunoreactivity. HES1 immunoreactivity was lacking altogether in 46% of the tumors, and in the remaining lesions its expression was weak and confined to the cytoplasm. In the nontumorous pancreatic endocrine cells, weak nuclear expression of HES1 as well as of HEY1 and NOTCH1 was observed. There was a significant positive correlation between NOTCH1 and HES1 mRNA levels, but no indication that HES1 was inhibiting ASCL1 transcription was found. No nuclear expression of HES1 was found in the tumors. This lack of nuclear expression of HES1 may contribute to the abundance of ASCL1 and to tumorigenesis in the endocrine pancreas.
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| 9. |
- Lejonklou, Margareta Halin, 1966-, et al.
(författare)
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Effects of Low-Dose Developmental Bisphenol A Exposure on Metabolic Parameters and Gene Expression in Male and Female Fischer 344 Rat Offspring.
- 2017
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Ingår i: Journal of Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 125:6
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Bisphenol A (BPA) is an endocrine-disrupting chemical that may contribute to development of obesity and metabolic disorders. Humans are constantly exposed to low concentrations of BPA, and studies support that the developmental period is particularly sensitive.OBJECTIVES: The aim was to investigate the effects of low-dose developmental BPA exposure on metabolic parameters in male and female Fischer 344 (F344) rat offspring.METHODS: Pregnant F344 rats were exposed to BPA via their drinking water, corresponding to (BPA0.5; ) or (BPA50; ), from gestational day (GD) 3.5 until postnatal day (PND) 22, and controls were given vehicle (). Body weight (BW), adipose tissue, liver (weight, histology, and gene expression), heart weight, and lipid profile were investigated in the 5-wk-old offspring.RESULTS: Males and females exhibited differential susceptibility to the different doses of BPA. Developmental BPA exposure increased plasma triglyceride levels ( compared with , females BPA50 ; compared with , males BPA0.5 ) in F344 rat offspring compared with controls. BPA exposure also increased adipocyte cell density by 122% in inguinal white adipose tissue (iWAT) of female offspring exposed to BPA0.5 compared with controls ( number of adipocytes/HPF compared with number of adipocytes/HPF; ) and by 123% in BPA0.5 females compared with BPA50 animals ( number of adipocytes/high power field (HPF) compared with number of adipocytes/HPF; ). In iWAT of male offspring, adipocyte cell density was increased by 129% in BPA50-exposed animals compared with BPA0.5-exposed animals ( number of adipocytes/HPF compared with number of adipocytes/HPF; ). Furthermore, the expression of genes involved in lipid and adipocyte homeostasis was significantly different between exposed animals and controls depending on the tissue, dose, and sex.CONCLUSIONS: Developmental exposure to of BPA, which is 8-10 times lower than the current preliminary EFSA (European Food Safety Authority) tolerable daily intake (TDI) of and is within the range of environmentally relevant levels, was associated with sex-specific differences in the expression of genes in adipose tissue plasma triglyceride levels in males and adipocyte cell density in females when F344 rat offspring of dams exposed to BPA at were compared with the offspring of unexposed controls.
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| 10. |
- Lejonklou, Margareta Halin, et al.
(författare)
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Neurogenin 3 and neurogenic differentiation 1 are retained in the cytoplasm of multiple endocrine neoplasia type 1 islet and pancreatic endocrine tumor cells
- 2009
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Ingår i: Pancreas. - 0885-3177 .- 1536-4828. ; 38:3, s. 259-266
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES:To investigate if transcription factors involved in pancreatic differentiation and regeneration are present in pancreatic endocrine tumors and if they are differentially expressed in normal pancreas compared with multiple endocrine neoplasia type 1 (MEN1) nontumorous pancreas.METHODS:The expression of neurogenin 3 (NEUROG3), neurogenic differentiation 1 (NEUROD1), POU class 3 homeobox 4 (POU3F4), pancreatic duodenal homeobox factor 1 (PDX1), ribosomal protein L10 (RPL10), delta-like 1 homolog (Drosophila; DLK1), and menin was analyzed by immunohistochemistry in normal pancreas and pancreatic endocrine tumors from 6 patients with MEN1 and 16 patients with sporadic tumors, as well as pancreatic specimens from Men1 heterozygous and wild type mice. Quantitative polymerase chain reaction was performed in a subset of human tumors.RESULTS:Tumors and MEN1 nontumorous endocrine cells showed a prominent cytoplasmatic NEUROG3 and NEUROD1 expression. These factors were significantly more expressed in the cytoplasm of Men1 heterozygous mouse islet cells compared with wild type islets; the latter showed an exclusively nuclear reactivity. The degree of Pou3f4, Rpl10, and Dlk1 immunoreactivities differed significantly between islets of heterozygous and wild type mice. The expressions of RPL10 and NEUROD1 were prominent in the MEN1 human and heterozygous mouse exocrine pancreas. Insulinomas had significantly higher PDX1 and DLK1 messenger RNA levels compared with other tumor types.CONCLUSIONS: Transcription factors involved in pancreatic development show altered expression and subcellular localization in MEN1 nontumorous pancreas and pancreatic endocrine tumors.
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