Maternal Exposure to Bisphenol-A During Pregnancy Increases Pancreatic β-Cell Growth During Early Life in Male Mice Offspring.
Alterations during development of metabolic key organs such as the endocrine pancreas affect the phenotype later in life. There is evidence that in utero or perinatal exposure to bisphenol-A (BPA) leads to impaired glucose metabolism during adulthood. However, how BPA exposure during pregnancy affects pancreatic β-cell growth and function in offspring during early life has not been explored. We exposed pregnant mice to either vehicle (control) or BPA (10 and 100 μg/kg·d, BPA10 and BPA100) and examined offspring on postnatal days (P) P0, P21, P30, and P120. BPA10 and BPA100 mice presented lower birth weight than control and subsequently gained weight until day 30. At that age, concentration of plasma insulin, C-peptide, and leptin were increased in BPA-exposed animals in the nonfasting state. Insulin secretion and content were diminished in BPA10 and maintained in BPA100 compared with control. A global gene expression analysis indicated that genes related with cell division were increased in islets from BPA-treated animals. This was associated with an increase in pancreatic β-cell mass at P0, P21, and P30 together with increased β-cell proliferation and decreased apoptosis. On the contrary, at P120, BPA-treated animals presented either equal or decreased β-cell mass compared with control and altered fasting glucose levels. These data suggest that in utero exposure to environmentally relevant doses of BPA alters the expression of genes involved in β-cell growth regulation, incrementing β-cell mass/area, and β-cell proliferation during early life. An excess of insulin signaling during early life may contribute to impaired glucose tolerance during adulthood.
Institute of Bioengineering (M.G.-A. T.B., B.M., S.V., I.Q., A.Na.) and Department of Applied Biology (P.A.-M.), Miguel Hernández University of Elche, 03202 Elche, Alicante, Spain; Diabetes and Obesity Research Laboratory (J.-M.S., A.No.), Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic de Barcelona, 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (M.G.-A., P.A.-M., J.-M.S., T.B.-B., B.M., S.V.-P., A.No., I.Q., A.Na.), Spain; and Department of Basic Sciences of Health (G.M.-G.), Area of Biochemistry and Molecular Biology, Rey Juan Carlos University, 28922 Alcorcon, Madrid, Spain.
Marta
M
García-Arévalo
Institute of Bioengineering (M.G.-A. T.B., B.M., S.V., I.Q., A.Na.) and Department of Applied Biology (P.A.-M.), Miguel Hernández University of Elche, 03202 Elche, Alicante, Spain; Diabetes and Obesity Research Laboratory (J.-M.S., A.No.), Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic de Barcelona, 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (M.G.-A., P.A.-M., J.-M.S., T.B.-B., B.M., S.V.-P., A.No., I.Q., A.Na.), Spain; and Department of Basic Sciences of Health (G.M.-G.), Area of Biochemistry and Molecular Biology, Rey Juan Carlos University, 28922 Alcorcon, Madrid, Spain.
Paloma
P
Alonso-Magdalena
Institute of Bioengineering (M.G.-A. T.B., B.M., S.V., I.Q., A.Na.) and Department of Applied Biology (P.A.-M.), Miguel Hernández University of Elche, 03202 Elche, Alicante, Spain; Diabetes and Obesity Research Laboratory (J.-M.S., A.No.), Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic de Barcelona, 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (M.G.-A., P.A.-M., J.-M.S., T.B.-B., B.M., S.V.-P., A.No., I.Q., A.Na.), Spain; and Department of Basic Sciences of Health (G.M.-G.), Area of Biochemistry and Molecular Biology, Rey Juan Carlos University, 28922 Alcorcon, Madrid, Spain.
Joan-Marc
JM
Servitja
Institute of Bioengineering (M.G.-A. T.B., B.M., S.V., I.Q., A.Na.) and Department of Applied Biology (P.A.-M.), Miguel Hernández University of Elche, 03202 Elche, Alicante, Spain; Diabetes and Obesity Research Laboratory (J.-M.S., A.No.), Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic de Barcelona, 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (M.G.-A., P.A.-M., J.-M.S., T.B.-B., B.M., S.V.-P., A.No., I.Q., A.Na.), Spain; and Department of Basic Sciences of Health (G.M.-G.), Area of Biochemistry and Molecular Biology, Rey Juan Carlos University, 28922 Alcorcon, Madrid, Spain.
Talía
T
Boronat-Belda
Institute of Bioengineering (M.G.-A. T.B., B.M., S.V., I.Q., A.Na.) and Department of Applied Biology (P.A.-M.), Miguel Hernández University of Elche, 03202 Elche, Alicante, Spain; Diabetes and Obesity Research Laboratory (J.-M.S., A.No.), Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic de Barcelona, 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (M.G.-A., P.A.-M., J.-M.S., T.B.-B., B.M., S.V.-P., A.No., I.Q., A.Na.), Spain; and Department of Basic Sciences of Health (G.M.-G.), Area of Biochemistry and Molecular Biology, Rey Juan Carlos University, 28922 Alcorcon, Madrid, Spain.
Beatriz
B
Merino
Institute of Bioengineering (M.G.-A. T.B., B.M., S.V., I.Q., A.Na.) and Department of Applied Biology (P.A.-M.), Miguel Hernández University of Elche, 03202 Elche, Alicante, Spain; Diabetes and Obesity Research Laboratory (J.-M.S., A.No.), Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic de Barcelona, 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (M.G.-A., P.A.-M., J.-M.S., T.B.-B., B.M., S.V.-P., A.No., I.Q., A.Na.), Spain; and Department of Basic Sciences of Health (G.M.-G.), Area of Biochemistry and Molecular Biology, Rey Juan Carlos University, 28922 Alcorcon, Madrid, Spain.
Sabrina
S
Villar-Pazos
Institute of Bioengineering (M.G.-A. T.B., B.M., S.V., I.Q., A.Na.) and Department of Applied Biology (P.A.-M.), Miguel Hernández University of Elche, 03202 Elche, Alicante, Spain; Diabetes and Obesity Research Laboratory (J.-M.S., A.No.), Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic de Barcelona, 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (M.G.-A., P.A.-M., J.-M.S., T.B.-B., B.M., S.V.-P., A.No., I.Q., A.Na.), Spain; and Department of Basic Sciences of Health (G.M.-G.), Area of Biochemistry and Molecular Biology, Rey Juan Carlos University, 28922 Alcorcon, Madrid, Spain.
Gema
G
Medina-Gómez
Institute of Bioengineering (M.G.-A. T.B., B.M., S.V., I.Q., A.Na.) and Department of Applied Biology (P.A.-M.), Miguel Hernández University of Elche, 03202 Elche, Alicante, Spain; Diabetes and Obesity Research Laboratory (J.-M.S., A.No.), Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic de Barcelona, 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (M.G.-A., P.A.-M., J.-M.S., T.B.-B., B.M., S.V.-P., A.No., I.Q., A.Na.), Spain; and Department of Basic Sciences of Health (G.M.-G.), Area of Biochemistry and Molecular Biology, Rey Juan Carlos University, 28922 Alcorcon, Madrid, Spain.
Anna
A
Novials
Institute of Bioengineering (M.G.-A. T.B., B.M., S.V., I.Q., A.Na.) and Department of Applied Biology (P.A.-M.), Miguel Hernández University of Elche, 03202 Elche, Alicante, Spain; Diabetes and Obesity Research Laboratory (J.-M.S., A.No.), Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic de Barcelona, 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (M.G.-A., P.A.-M., J.-M.S., T.B.-B., B.M., S.V.-P., A.No., I.Q., A.Na.), Spain; and Department of Basic Sciences of Health (G.M.-G.), Area of Biochemistry and Molecular Biology, Rey Juan Carlos University, 28922 Alcorcon, Madrid, Spain.
Ivan
I
Quesada
Institute of Bioengineering (M.G.-A. T.B., B.M., S.V., I.Q., A.Na.) and Department of Applied Biology (P.A.-M.), Miguel Hernández University of Elche, 03202 Elche, Alicante, Spain; Diabetes and Obesity Research Laboratory (J.-M.S., A.No.), Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic de Barcelona, 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (M.G.-A., P.A.-M., J.-M.S., T.B.-B., B.M., S.V.-P., A.No., I.Q., A.Na.), Spain; and Department of Basic Sciences of Health (G.M.-G.), Area of Biochemistry and Molecular Biology, Rey Juan Carlos University, 28922 Alcorcon, Madrid, Spain.
Angel
A
Nadal
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001559:Benzhydryl Compounds / Q000633:toxicity*; D002096:C-Peptide / Q000097:blood; D049109:Cell Proliferation / Q000187:drug effects; D005215:Fasting / Q000097:blood; D005260:Female; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D020738:Leptin / Q000097:blood; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects*; D051379:Mice; D010636:Phenols / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D014599:Uterus / Q000187:drug effects; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D002096:C-Peptide; D007328:Insulin; D020738:Leptin; D010636:Phenols; C006780:bisphenol A; D000098826:Bisphenol A Compounds