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Lejonklou, Margareta Halin
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Publications (10 of 28) Show all publications
Manukyan, L., Dunder, L., Lind, P. M., Bergsten, P. & Lejonklou, M. H. (2019). Developmental exposure to a very low dose of bisphenol A induces persistent islet insulin hypersecretion in Fischer 344 rat offspring. Environmental Research, 172, 127-136
Open this publication in new window or tab >>Developmental exposure to a very low dose of bisphenol A induces persistent islet insulin hypersecretion in Fischer 344 rat offspring
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2019 (English)In: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 172, p. 127-136Article in journal (Refereed) Published
Abstract [en]

Background: In children with obesity, accentuated insulin secretion has been coupled with development of type 2 diabetes mellitus (T2DM). Bisphenol A (BPA) is a chemical with endocrine- and metabolism-disrupting properties which can be measured in a majority of the population. Exposure to BPA has been associated with the development of metabolic diseases including T2DM.

Objective: The aim of this study was to investigate if exposure early in life to an environmentally relevant low dose of BPA causes insulin hypersecretion in rat offspring.

Methods: Pregnant Fischer 344 rats were exposed to 0.5 (BPA0.5) or 50 (BPA50) jig BPA/kg BW/day via drinking water from gestational day 3.5 until postnatal day 22. Pancreata from dams and 5- and 52-week-old offspring were procured and islets were isolated by collagenase digestion. Glucose-stimulated insulin secretion and insulin content in the islets were determined by ELISA.

Results: Basal (5.5 mM glucose) islet insulin secretion was not affected by BPA exposure. However, stimulated (11 mM glucose) insulin secretion was enhanced by about 50% in islets isolated from BPA0.5-exposed 5- and 52 week-old female and male offspring and by 80% in islets from dams, compared with control. In contrast, the higher dose, BPA50, reduced stimulated insulin secretion by 40% in both 5- and 52-week-old female and male offspring and dams, compared with control.

Conclusion: A BPA intake 8 times lower than the European Food Safety Authority's (EFSA's) current tolerable daily intake (TDI) of 4 mu g/kg BW/day of BPA delivered via drinking water during gestation and early development causes islet insulin hypersecretion in rat offspring up to one year after exposure. The effects of BPA exposure on the endocrine pancreas may promote the development of metabolic disease including T2DM.

Place, publisher, year, edition, pages
ACADEMIC PRESS INC ELSEVIER SCIENCE, 2019
Keywords
Bisphenol A, Endocrine disruptor, Fischer 344 rats, Insulin hypersecretion, Islets of Langerhans
National Category
Occupational Health and Environmental Health
Identifiers
urn:nbn:se:uu:diva-387967 (URN)10.1016/j.envres.2019.02.009 (DOI)000468377500014 ()30782532 (PubMedID)
Funder
Swedish Research Council Formas, 216-2012-475Swedish Diabetes Association, DIA 2016-146Ernfors Foundation, 170504
Available from: 2019-06-27 Created: 2019-06-27 Last updated: 2019-06-27Bibliographically approved
Lind, T., Lejonklou, M. H., Dunder, L., Kushnir, M. M., Öhman-Mägi, C., Larsson, S., . . . Lind, P. M. (2019). Developmental low-dose exposure to bisphenol A induces chronic inflammation, bone marrow fibrosis and reduces bone stiffness in female rat offspring only. Environmental Research, 177, Article ID 108584.
Open this publication in new window or tab >>Developmental low-dose exposure to bisphenol A induces chronic inflammation, bone marrow fibrosis and reduces bone stiffness in female rat offspring only
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2019 (English)In: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 177, article id 108584Article in journal (Refereed) Published
Abstract [en]

Background: Developmental exposure to low doses of the endocrine disruptor bisphenol A (BPA) is known to alter bone tissue in young rodents, although how bone tissue is affected in aged animals is not well known. We have recently shown that low-dose developmental exposure to BPA increases procollagen type I N-terminal propeptide (P1NP) levels, a peptide formed during type 1 collagen synthesis, in plasma of 5-week-old female rat offspring while male offspring showed reduced bone size.

Objective: To analyze offspring bone phenotype at 52 weeks of age and clarify whether the BPA-induced increase in P1NP levels at 5 weeks is an early sign of bone marrow fibrosis development.

Methods: As in our 5-week study, pregnant Fischer 344 rats were exposed to BPA via drinking water corresponding to 0.5 mu g/kg BW/day (BPA0.5), which is in the range of human daily exposure, or 50 mu g/kg BW/day (BPA50) from gestational day 3.5 until postnatal day 22. Controls were given only vehicle. The offspring were sacrificed at 52 weeks of age. Bone effects were analyzed using peripheral quantitative and micro-computed tomography (microCT), 3-point bending test, plasma markers and histological examination.

Results: Compared to a smaller bone size at 5 weeks, at the age of 52 weeks, femur size in male offspring had been normalized in developmentally BPA-exposed rats. The 52-week-old female offspring showed, like the 5-week-old siblings, higher plasma P1NP levels compared to controls but no general increasing bone growth or strength. However, 2 out of 14 BPA-exposed female offspring bones developed extremely thick cortices later in life, discovered by systematic in vivo microCT scanning during the study. This was not observed in male offspring or in female controls. Biomechanical testing revealed that both doses of developmental BPA exposure reduced femur stiffness only in female offspring. In addition, histological analysis showed an increased number of fibrotic lesions only in the bone man ow of female rat offspring developmentally exposed to BPA. In line with this, plasma markers of inflammation, Tnf (in BPA0.5) and Timpl (in BPA50) were increased exclusively in female offspring.

Conclusions: Developmental BPA exposure at an environmentally relevant concentration resulted in female specific effects on bone as well as on plasma biomarkers of collagen synthesis and inflammation. Even a dose approximately eight times lower than the current temporary EFSA human tolerable daily intake of 4 mu g/kg BW/day, appeared to induce bone stiffness reduction, bone man ow fibrosis and chronic inflammation in female rat offspring later in life.

Keywords
Bisphenol A, Female offspring, P1NP, Fibrosis, Bone
National Category
Occupational Health and Environmental Health
Identifiers
urn:nbn:se:uu:diva-394951 (URN)10.1016/j.envres.2019.108584 (DOI)000484645500056 ()31326715 (PubMedID)
Funder
Swedish Research Council Formas, 216-2012-475
Available from: 2019-10-21 Created: 2019-10-21 Last updated: 2019-10-21Bibliographically approved
Dunder, L., Lejonklou, M. H., Lind, L., Risérus, U. & Lind, P. M. (2018). Low-dose developmental bisphenol A exposure alters fatty acid metabolism in Fischer 344 rat offspring. Environmental Research, 166, 117-129
Open this publication in new window or tab >>Low-dose developmental bisphenol A exposure alters fatty acid metabolism in Fischer 344 rat offspring
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2018 (English)In: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 166, p. 117-129Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
BPA, Bisphenol A, Metabolism disrupting chemical, Low-dose exposure, FA, Fatty acid, SCD-1, Stearoyl-CoA desaturase 1, Adipose tissue
National Category
Occupational Health and Environmental Health
Identifiers
urn:nbn:se:uu:diva-363414 (URN)10.1016/j.envres.2018.05.023 (DOI)000445318200016 ()29885613 (PubMedID)
Funder
Swedish Research Council Formas, 216-2012-475
Available from: 2018-10-18 Created: 2018-10-18 Last updated: 2018-10-18Bibliographically approved
Spörndly-Nees, E., Boberg, J., Ekstedt, E., Holm, L., Fakhrzadeh, A., Dunder, L., . . . Lind, P. M. (2018). Low-dose exposure to Bisphenol A during development has limited effects on male reproduction in midpubertal and aging Fischer 344 rats.. Reproductive Toxicology, 81, 196-206
Open this publication in new window or tab >>Low-dose exposure to Bisphenol A during development has limited effects on male reproduction in midpubertal and aging Fischer 344 rats.
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2018 (English)In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 81, p. 196-206Article in journal (Refereed) Published
Abstract [en]

Low doses of Bisphenol A (BPA) during development may affect reproduction. In this study, Fischer 344 rats were exposed to 0.5 or 50 μg BPA/kg bw/day via drinking water from gestational day 3.5 to postnatal day 22. Anogenital distance, organ weight, histopathology of reproductive organs, hormone analysis and sperm morphology were evaluated in male offspring. In this study no major effects of BPA on male reproduction in midpubertal (postnatal day 35) or adult (12-month-old) rats were revealed, apart from a higher prevalence of mild inflammatory cell infiltrate in cauda epididymis in adult rats exposed to 50 μg BPA/kg bw/day. No BPA-related effects on sexual development were seen but care should be taken when evaluating histopathology in midpuberty testis due to large morphological variation. Results from the present study show no major signs of altered male reproduction in rats exposed to low doses of BPA during gestation and lactation.

Keywords
Aging, Bisphenol A, Developmental exposure, Endocrine disrupting chemical, Histopathology, Low dose, Male reproduction, Puberty
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-369354 (URN)10.1016/j.reprotox.2018.08.007 (DOI)000448635200024 ()30121228 (PubMedID)
Funder
Swedish Research Council Formas, 216-2012-475
Note

De två sista författarna delar sistaförfattarskapet.

Available from: 2018-12-12 Created: 2018-12-12 Last updated: 2018-12-19Bibliographically approved
Alavian-Ghavanini, A., Lin, P.-I., Lind, P. M., Rimfors, S. R., Lejonklou, M. H., Dunder, L., . . . Rueegg, J. (2018). Prenatal Bisphenol A Exposure is Linked to Epigenetic Changes in Glutamate Receptor Subunit Gene Grin2b in Female Rats and Humans. Scientific Reports, 8, Article ID 11315.
Open this publication in new window or tab >>Prenatal Bisphenol A Exposure is Linked to Epigenetic Changes in Glutamate Receptor Subunit Gene Grin2b in Female Rats and Humans
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 11315Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-361996 (URN)10.1038/s41598-018-29732-9 (DOI)000439965200008 ()30054528 (PubMedID)
Funder
EU, Horizon 2020, 634880Swedish Research Council, 216-2012-475Swedish Research Council, 210-2012-1502Swedish Research Council, 216-2013-1966
Available from: 2018-10-08 Created: 2018-10-08 Last updated: 2018-10-08Bibliographically approved
Lejonklou, M. H., Dunder, L., Bladin, E., Pettersson, V., Rönn, M., Lind, L., . . . Lind, P. M. (2017). Effects of Low-Dose Developmental Bisphenol A Exposure on Metabolic Parameters and Gene Expression in Male and Female Fischer 344 Rat Offspring.. Journal of Environmental Health Perspectives, 125(6), Article ID 067018.
Open this publication in new window or tab >>Effects of Low-Dose Developmental Bisphenol A Exposure on Metabolic Parameters and Gene Expression in Male and Female Fischer 344 Rat Offspring.
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2017 (English)In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 125, no 6, article id 067018Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Occupational Health and Environmental Health Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-326311 (URN)10.1289/EHP505 (DOI)000413788400027 ()28657538 (PubMedID)
Available from: 2017-07-05 Created: 2017-07-05 Last updated: 2018-01-31Bibliographically approved
Lind, T., Lejonklou, M. H., Dunder, L., Rasmusson, A., Larsson, S., Melhus, H. & Lind, P. M. (2017). Low-dose developmental exposure to bisphenol A induces sex-specific effects in bone of Fischer 344 rat offspring. Environmental Research, 159, 61-68, Article ID S0013-9351(17)30727-2.
Open this publication in new window or tab >>Low-dose developmental exposure to bisphenol A induces sex-specific effects in bone of Fischer 344 rat offspring
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2017 (English)In: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 159, p. 61-68, article id S0013-9351(17)30727-2Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Bisphenol A (BPA) is a component of polycarbonate plastics to which humans are regularly exposed at low levels, and an endocrine disruptor with effects on several hormonal systems. Bone is a sensitive hormone target tissue, and we have recently shown that in utero and lactational exposure to 25µg BPA/kg BW/day alters femoral geometry in rat offspring.

OBJECTIVE: To investigate bone effects in rat offspring after developmental exposure to a BPA dose in the range of human daily exposure (0.1-1.5µg/kg BW/day) as well as a dose to corroborate previous findings.

METHODS: Pregnant Fischer 344 rats were exposed to BPA via drinking water corresponding to 0.5µg/kg BW/day: [0.5], (n=21) or 50µg/kg BW/day: [50], (n = 16) from gestational day 3.5 until postnatal day 22, while controls were given only vehicle (n = 25). The offspring was sacrificed at 5 weeks of age. Bone effects were analyzed using peripheral quantitative computed tomography (pQCT), the 3-point bending test, plasma markers of bone turnover, and gene expression in cortical bone and bone marrow.

RESULTS: Compared to controls, male offspring developmentally exposed to BPA had shorter femurs. pQCT analysis revealed effects in the [0.5] group, but not in the [50] group; BPA reduced both trabecular area (-3.9%, p < 0.01) and total cross sectional area (-4.1%, p < 0.01) of femurs in the [0.5] group, whereas no effects were seen on bone density. Conversely, bone length and size were not affected in female offspring. However, the procollagen type I N-terminal propeptide (P1NP), a peptide formed during type 1 collagen synthesis, was increased in plasma (42%: p < 0.01) in female offspring exposed to [0.5] of BPA, although collagen gene expression was not increased in bone. The biomechanical properties of the bones were not altered in either sex. Bone marrow mRNA expression was only affected in male offspring.

CONCLUSIONS: Developmental low-dose exposure to BPA resulted in sex-specific bone effects in rat offspring. A dose approximately eight times lower than the current temporary EFSA human tolerable daily intake of 4µg/kg BW/day, reduced bone length and size in male rat offspring. Long-term studies are needed to clarify whether the increased plasma levels of P1NP in female offspring reflect development of fibrosis.

Keywords
Bisphenol A, Bone geometry, Developmental exposure, Endocrine disruption, Low-dose effects
National Category
Occupational Health and Environmental Health
Identifiers
urn:nbn:se:uu:diva-336132 (URN)10.1016/j.envres.2017.07.020 (DOI)000413280500007 ()28772150 (PubMedID)
Funder
Swedish Research Council Formas, 216-2012-475
Available from: 2017-12-12 Created: 2017-12-12 Last updated: 2018-02-02Bibliographically approved
Klint, H., Lejonklou, M. H., Karimullina, E., Rönn, M., Lind, L., Lind, P. M. & Brittebo, E. (2017). Low-dose exposure to bisphenol A in combination with fructose increases expression of genes regulating angiogenesis and vascular tone in juvenile Fischer 344 rat cardiac tissue. Upsala Journal of Medical Sciences, 122(1), 20-27
Open this publication in new window or tab >>Low-dose exposure to bisphenol A in combination with fructose increases expression of genes regulating angiogenesis and vascular tone in juvenile Fischer 344 rat cardiac tissue
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2017 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 1, p. 20-27Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: Epidemiological studies report associations between exposure to the high-volume chemical and endocrine disruptor bisphenol A (BPA) and cardiovascular disorders, but there is a lack of experimental studies addressing the mechanisms of action of BPA on the cardiovascular system. In the present study, effects on markers for cardiovascular function of exposure to BPA and fructose in vivo in rat cardiac tissues, and of BPA exposure in human cardiomyocytes in vitro, were investigated.

MATERIALS: Juvenile female Fischer 344 rats were exposed to 5, 50, and 500 μg BPA/kg bodyweight/day in their drinking water from 5 to 15 weeks of age, in combination with 5% fructose. Further, cultured human cardiomyocytes were exposed to 10 nM BPA to 1 × 10(4) nM BPA for six hours. Expression of markers for cardiovascular function and BPA target receptors was investigated using qRT-PCR.

RESULTS: Exposure to 5 μg BPA/kg bodyweight/day plus fructose increased mRNA expression of Vegf, Vegfr2, eNos, and Ace1 in rat heart. Exposure of human cardiomyocytes to 1 × 10(4) nM BPA increased mRNA expression of eNOS and ACE1, as well as IL-8 and NFκβ known to regulate inflammatory response.

CONCLUSIONS: . Low-dose exposure of juvenile rats to BPA and fructose induced up-regulation of expression of genes controlling angiogenesis and vascular tone in cardiac tissues. The observed effects of BPA in rat heart were in line with our present and previous studies of BPA in human endothelial cells and cardiomyocytes. These findings may aid in understanding the mechanisms of the association between BPA exposure and cardiovascular disorders reported in epidemiological studies.

Keywords
Angiogenesis, bisphenol A, cardiomyocytes, cardiovascular disease, endocrine disruption, fructose, heart, vascular tone
National Category
Pharmacology and Toxicology General Practice
Identifiers
urn:nbn:se:uu:diva-311874 (URN)10.1080/03009734.2016.1225870 (DOI)000396476600003 ()27622962 (PubMedID)
Funder
Swedish Research Council Formas, 216-2009-972
Available from: 2017-01-03 Created: 2017-01-03 Last updated: 2018-01-13Bibliographically approved
Lejonklou, M. H., Christiansen, S., Örberg, J., Shen, L., Larsson, S., Boberg, J., . . . Lind, P. M. (2016). Low-dose developmental exposure to bisphenol A alters the femoral bone geometry in wistar rats. Chemosphere, 164, 339-346
Open this publication in new window or tab >>Low-dose developmental exposure to bisphenol A alters the femoral bone geometry in wistar rats
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2016 (English)In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 164, p. 339-346Article in journal (Refereed) Published
Abstract [en]

Background: Bisphenol A (BPA) is a chemical produced in large volumes for use in manufacturing of consumer products and industrial applications, and an endocrine disruptor known to affect several hormonal systems. Bone produces hormones and is additionally a sensitive hormone target tissue, and is thus potentially sensitive to low doses of endocrine disruptors such as BPA, especially during development. Methods: 110 pregnant Wistar rats were gavaged with 0; 25 mu g; 250 mu g; 5000 mu g or 50,000 mu g BPA/kg bodyweight (bw)/day from gestational day 7 until weaning at postnatal day 22. The three-month-old offspring were sacrificed and right femurs collected for length measurements, geometrical measurements by peripheral quantitative computed tomography (pQCT), as well as for analyses of biomechanical properties using the three-point-bending method. Results: The femur was elongated in female offspring of dams exposed to 25 or 5000 mu g BPA/kg bw/day (1.8% and 2.1%, respectively), and increased cortical thickness (4.7%) was observed in male offspring of dams exposed to 25 mu g BPA/kg bw/day, compared to controls (p < 0.005). The biomechanical properties of the bone were not significantly altered. Conclusions: In utero and lactational exposure to the lowest BPA dose used in this study altered femoral geometry in both male and female offspring. This was observed at 25 mu g BPA/kg bw/day, a dose lower than the Human Equivalent Dose (HED) applied by EFSA to set a temporary TDI (609 mu g BPA/kg bw/day), and far lower than the No-Observed-Adverse-Effect-Level (NOAEL) (5000 mu g BPA/kg bw/day) on which the US FDA TDI is based.

Keywords
Bisphenol A (BPA), Endocrine disrupting chemicals (EDCs), Low dose effects, Developmental exposure, Bone geometry, Bone biomechanics
National Category
Pharmacology and Toxicology Analytical Chemistry
Identifiers
urn:nbn:se:uu:diva-307506 (URN)10.1016/j.chemosphere.2016.08.114 (DOI)000385318200040 ()27592323 (PubMedID)
Funder
Swedish Research Council Formas, 216-2009-972; 216-2012-475
Available from: 2016-11-21 Created: 2016-11-17 Last updated: 2018-01-13Bibliographically approved
Barbu, A., Lejonklou, M. H. & Skogseid, B. (2016). Progranulin Stimulates Proliferation of Mouse Pancreatic Islet Cells and Is Overexpressed in the Endocrine Pancreatic Tissue of an MEN1 Mouse Model. Pancreas, 45(4), 533-540
Open this publication in new window or tab >>Progranulin Stimulates Proliferation of Mouse Pancreatic Islet Cells and Is Overexpressed in the Endocrine Pancreatic Tissue of an MEN1 Mouse Model
2016 (English)In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 45, no 4, p. 533-540Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: Progranulin (PGRN) promotes cell growth and cell cycle progression in several cell types and contributes to tumorigenesis in diverse cancers. We have recently reported PGRN expression in islets and tumors developed in an MEN1 transgenic mouse. Here we sought to investigate PGRN expression and regulation after exposure to hypoxia as well as its effects on pancreatic islet cells and neuroendocrine tumors (NETs) in MEN1 mice.

METHODS: Gene and protein expression were analyzed by quantitative polymerase chain reaction, immunohistochemistry, and Western blot. We also investigated PGRN expression in samples from patients carrying pancreatic NETs associated or not with the multiple endocrine neoplasia 1 syndrome, using enzyme-linked immunosorbent assay and immunohistochemistry analysis.

RESULTS: Progranulin is upregulated in tumors and islets of the MEN1 mouse as well as in the serum of patients with pancreatic NETs associated with glucagonoma syndrome. In normal mice islets and pancreatic tumors, PGRN expression was strongly potentiated by hypoxia. Progranulin promotes cell proliferation in islet cells and βTC-6 cells, a process paralleled by activation of the mitogen-activated protein kinase signaling cascade.

CONCLUSIONS: Our findings identify PGRN as an effective inducer of pancreatic islet cell proliferation and a possible important factor for pancreatic endocrine tumor development.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-273805 (URN)10.1097/MPA.0000000000000509 (DOI)000372350500008 ()26495792 (PubMedID)
Funder
Swedish Cancer Society, 110674Swedish Research Council, M-521-2011-3668Swedish Society for Medical Research (SSMF)Swedish Society of Medicine
Available from: 2016-01-18 Created: 2016-01-18 Last updated: 2018-01-10Bibliographically approved
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