BPA exposure during pregnancy: risk for gestational diabetes and diabetes following pregnancy

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1 BPA exposure during pregnancy: risk for gestational diabetes and diabetes following pregnancy Paloma Alonso-Magdalena Applied Biology Department and CIBERDEM, Miguel Hernández University, Elche, Spain

2 Pregnancy transiently drives women into a metabolic stress scenario that can determinate their health status in later life

3 - Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with onset or first recognition during pregnancy - Aproximately 7% of all pregnancies are complicated by GDM resulting in more than 200,000 cases anually.

4 RISKS FACTORS FOR GDM Age History of gestational diabetes Obesity Ethnicity Sedentary lifestyle History of smoking

5 CONSEQUENCES OF GESTATIONAL DIABETES IN THE LONG TERM.

6 THROUGH THE LOOKING GLASS - During post-partum most of the women return to euglycemic state, however carbohydrate intolerance can return with age. - Women with GDM are at increased risk for the development of diabetes, usually type 2, after pregnancy. Glucose intolerance during pregnancy as a predictor of maternal long -term health

7 ENDOCRINE DISRUPTORS have been defined as exogenous substances that alter function(s) of the endocrine system and consequently cause adverse health effects in an intact organism, its progeny, or subpopulations The International Program for Chemical Safety

8 WHAT HAPPEN IF MOTHERS ARE EXPOSED TO THESE COMPOUNDS DURING PREGNANCY?

9 RISKS FACTORS FOR GDM AND LONG-TERM COMPLICATIONS Age History of gestational diabetes Obesity ENDOCRINE DISRUPTOR CHEMICALS Ethnicity Sedentary lifestyle History of smoking PCOs

10 The case of bisphenol A: What is and where is found BPA? Welshons, W. V. et al. Endocrinology 2006

11 BISPHENOL-A CONCENTRATION IN HUMAN SAMPLES: BPA has been detected in 93% of the urine samples in USA (Calafat et al, 2008) ng/ml ( nm) unconjugated BPA in human blood from adult men and women (Vandenberg et al, EHP 2010) BPA levels detected in amniotic fluid, neonatal blood, placenta, cord blood and human breast milk.

12 Bisphenol-A action on pregnant mice BPA treatment End points measured at pregnancy days 17 and 18 BPA 10 mg/kg/day BPA 100 mg/kg/day Alonso-Magdalena et al, EHP 2010

13 Glycaemia (mg/dl) Pregnancy BPA treatment End points measured at pregnancy days 17 and 18 A VEHICLE BPA10 mg/kg/day BPA100 mg/kg/day Time after glucose injection (min) B AUC mg/dl.min * Vehicle BPA10 BPA100 Alonso-Magdalena et al, EHP 2010 GLUCOSE TOLERANCE TEST

14 Insulin signaling in BPA-10 pregnant treated mice pakt (Threonine 308 ) AU pakt (Threonine 308 ) AU Liver Skeletal muscle A B pakt pakt 1.6 * 2.5 * * Control BPA10 Control BPA10 Bisphenol-A alters glucose and lipid metabolism during pregnancy Alonso-Magdalena et al, Environ Health Perspect 2010

15 EVOLUTION OF THE MOTHER AFTER DELIVERY 3 Months after labor 4 Months after labor 5 Months after labor 6 Months after labor 7 Months after labor

16 Glycemia (mg/dl) Glycemia (mg/dl) Glycemia (mg/dl) Glycemia (mg/dl) GLUCOSE TOLERANCE TEST in the mother after labor A C 220 Control BPA BPA MONTHS POSTPARTUM Time (min) 5 MONTHS POSTPARTUM * * Time (min) Alonso-Magdalena P. et al Endocrinology 2015 B D MONTHS POSTPARTUM * * Time (min) 6 MONTHS POSTPARTUM * * * * Time (min)

17 % Glycemia (mg/dl) % Glycemia (mg/dl) % Glycemia (mg/dl) % Glycemia (mg/dl) A INSULIN TOLERANCE TEST in the mother after labor 3 MONTHS POSTPARTUM Control BPA10 BPA100 B MONTHS POSTPARTUM C Time (min) 5 MONTHS POSTPARTUM * * * Time (min) Alonso-Magdalena P. et al Endocrinology 2015 D * * Time (min) 6 MONTHS POSTPARTUM * * * * Time (min)

18 Insulin secretion (% Insulin content) (miu Insulin /mg protein) Insulin (ng/ml) Insulin secretion (miu Insulin/mg protein) Seven months after labor mothers that have been treated with BPA show a decline of pancreatic b-cell function A Plasma insulin levels Glucose-stimulated insulin secretion B * * 600 Control 500 BPA10 BPA * ** 0.0 Control BPA10 BPA G 8G 16G C * * 3G 8G 16G Alonso-Magdalena P. et al Endocrinology 2015 D Insulin content Insulin content *** Control BPA10 BPA100

19 % Proliferation b-cell % Apoptosis b-cell Relative b-cell mass (% per pancreas area) b-cell mass (mg) b-cell mass (mg/ g bw) Seven months after labor mothers that have been treated with BPA show reduced b-cell mass, reduced b-cell proliferation and increase rate of apoptosis A B C *** *** 2 *** *** *** *** 0.0 Control BPA10 BPA100 0 Control BPA10 BPA Control BPA10 BPA100 Control D E BPA * * * * 0.00 Control BPA10 BPA Control BPA10 BPA100 Alonso-Magdalena P. et al Endocrinology 2015

20 % Cyclin D2 % p16 % p53 Cyclin D2/b-tubulin CDK-4/b-tubulin PDX-1/b-tubulin Cyclin D2 CDK-4 PDX b-tubulin b-tubulin A B C * Control BPA * Control BPA b-tubulin Control BPA10 D E F * * ** *** ** 0 Control BPA10 BPA100 0 Control BPA10 BPA100 0 Control BPA10 BPA100 Alonso-Magdalena P. et al Endocrinology 2015

21 BPA exposure in mice during pregnancy resulted in an impairment of glucose tolerance and decreased insulin sensitivity in mothers. Alterations on glucose metabolism were resolved after parturition but were triggered again some months later Six months after delivery those moms that have been treated with BPA during pregnancy exhibited marked glucose intolerance and insulin resistance Seven months after delivery they showed decrease b-cell function, b- cell mass and increased apoptosis. They also showed an altered expression of several cell cycle regulators. BPA exposure during pregnancy could be considered a new risk factor for the deterioration of maternal glucose metabolism and the increased occurrence of diabetes

22 Figure 1 Pregnancy-like actions of endocrine disrupting chemicals on islet function and glucose homeostasis Alonso-Magdalena, P. et al. (2011) Endocrine disruptors in the etiology of type 2 diabetes mellitus Nat. Rev. Endocrinol. doi: /nrendo

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