Bisphenol-A Treatment During Pregnancy in Mice: A New Window of Susceptibility for the Development of Diabetes in Mothers Later in Life

• Published in: Endocrinology (Philadelphia) Vol. 156; no. 5; pp. 1659 - 1670
• Main Authors: Alonso-Magdalena, Paloma, García-Arévalo, Marta, Quesada, Iván, Nadal, Ángel
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01.05.2015
• Subjects: Animals; Apoptosis - drug effects; Benzhydryl Compounds - pharmacology; Blood Glucose - metabolism; Cell Proliferation - drug effects; Diabetes Mellitus, Type 2 - etiology; Disease Susceptibility; Endocrine Disruptors - pharmacology; Estrogens, Non-Steroidal - pharmacology; Female; Gene Expression Regulation - drug effects; Glucose Tolerance Test; Insulin; Insulin Resistance; Insulin-Secreting Cells - drug effects; Islets of Langerhans - drug effects; Maternal Exposure; Mice; Phenols - pharmacology; Pregnancy; RNA, Messenger - metabolism
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2014-1952

Evidence now exists supporting the hypothesis that endocrine-disrupting chemicals (EDCs) can harmfully impact glucose metabolism. Thus, EDCs are beginning to be considered important contributors to the increased incidence of diabetes, obesity, or both. The possible effect of exposure to EDCs during pregnancy on glucose homeostasis in mothers later in life is presently unknown. Here we show that several months after delivery, mothers treated with the widespread EDC bisphenol-A (BPA) during gestation, at environmentally relevant doses, exhibit profound glucose intolerance and altered insulin sensitivity as well as increased body weight. These mice presented a decreased insulin secretion both in vivo and in vitro together with reduced pancreatic β-cell mass. The proliferation capacity was decreased in association with a diminished expression of the cell cycle activators: cyclin D2 and cyclin-dependent kinase-4. In addition, the rate of β-cells apoptosis was increased as well as the expression of the cell cycle inhibitors p16 and p53. Conversely, no effects on glucose metabolism or insulin sensitivity were observed when female nonpregnant mice were treated with BPA at the same doses. Taken together, these findings reveal that BPA exposure during gestation has harmful long-term implications in glucose metabolism for the mother. This finding highlights a new window of susceptibility for EDC exposure that may be important for the development of type 2 diabetes.