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Maternal Bisphenol A Programs Offspring Metabolic Syndrome

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Maternal Bisphenol A Programs Offspring Metabolic Syndrome

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by the Collaborative on Health and the Environment

On this call Drs. Ross and Desai presented evidence that prenatal exposure to EDCs, specifically the plastic component Bisphenol A, can increase the relative risk of adult obesity and metabolic syndrome. They also discussed the significance of these findings for neonatal and childhood care, and the need for strategies for the prevention and therapy of obesity to address programming effects of the early life environment.

Sources: http://www.healthandenvironment.org/partnership_calls/15308

by the Collaborative on Health and the Environment

On this call Drs. Ross and Desai presented evidence that prenatal exposure to EDCs, specifically the plastic component Bisphenol A, can increase the relative risk of adult obesity and metabolic syndrome. They also discussed the significance of these findings for neonatal and childhood care, and the need for strategies for the prevention and therapy of obesity to address programming effects of the early life environment.

Sources: http://www.healthandenvironment.org/partnership_calls/15308

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Maternal Bisphenol A Programs Offspring Metabolic Syndrome

  1. 1. Maternal Bisphenol A Programs Offspring Metabolic Syndrome Michael G. Ross, M.D., M.P.H. and Mina Desai, Ph.D. Department of Obstetrics & Gynecology Los Angeles Biomedical Institute at Harbor-UCLA Medical Center
  2. 2. Metabolic Syndrome •Traits: •Obesity •Hypertension •Type 2 diabetes mellitus •Dyslipidemia •Mortality: Leading cause of death in the United States •Obesity: U.S. adults 65% overweight, 31% obese, Childhood obesity 20% •Hypertension: 29% of U.S. population •Diabetes: 27% of U.S. population
  3. 3. 2000 Obesity Trends* Among U.S. Adults From 1990 to 2010 (BRFSS; *BMI 30, or about 30 lbs. overweight for 5’4” person) 2010 1990 No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%
  4. 4. Etiology of Obesity Food Availability High Fat Diets Reduced Energy Expenditure Propensity for Obesity Developmental Programming
  5. 5. Developmental Programming Altered cell number and differentiation Modified gene expression altered function Fetal Nutrition, Stress ? Environmental Toxins
  6. 6. Bisphenol A (BPA) All foods Infant formula Pasta Vegetable Soup Beans Tuna Fruit Meal replace Soda Milk products 0 20 40 60 80 100 Percent of canned foods that exceed safety threshold Within factor of 5 Within factor of 5-10 Within factor of 10-100 BPA in a single serving compared to toxic dose
  7. 7. BPA: Endocrine Disruptor BPA BPA
  8. 8. NHANES: BPA Levels during Pregnancy Breast Milk 1.1 ng/ml Maternal Serum 1 - 2 ng/ml Placenta 1 – 105 ng/ml Amniotic Fluid 8.3 – 8.7 ng/ml Fetal Serum 0.2 – 9.2 ng/ml
  9. 9. Models of BPA-Induced Fetal Programming •In vivo maternal BPA exposure –Offspring phenotype –In utero effects on fetal appetite and adipose development •In vitro fetal BPA exposure –Effect on neural stem cells –Effect on adipose tissue development
  10. 10. Maternal Bisphenol A (BPA) OFFSPRING • Litter size: Culled to 4 males and 4 females at birth • Nursing: All pups nursed by same dams until p21 • Weaning: At p21 to ad libitum food and BPA-free water
  11. 11. Maternal BPA: Offspring Body Weights -1 Day 6 Month Increased Body Weights in Males SYSBP_M Control BPA Body Wight (g) 0 2 4 6 8 Control BPA MALES FEMALES Control BPA Body Wight (g) 0 100 200 300 400 500 600 MALES Control BPA FEMALES *
  12. 12. Maternal BPA: Body Fat of 6 Month Offspring Control BPA Body Fat (%) 0 5 10 15 20 Control BPA MALES FEMALES * Increased Body Fat in Males
  13. 13. Major Contributors of Obesity Food Intake Fat
  14. 14. Appetite Regulation PVN ARC POMC NPY
  15. 15. ARC Nucleus Development •ARC cells arise from Neural Stem Cells in periventricular region •Appetite (NPY) and Satiety (POMC) neurons populate the ARC during fetal life and this continues to develop during postnatal life Appetite Regions Neural Stem Cells 3V ARC
  16. 16. Hypothesis of Enhanced Appetite Appetite (NPY) neurons Satiety (POMC) neurons Increased Food Intake Fetal BPA exposure
  17. 17. Hypothalamic Neurospheres Undifferentiated Early Differentiation
  18. 18. NSC Proliferative & Differention Factors (Nestin)
  19. 19. Methods: NSC In Utero BPA Exposure Hypothalamic NSCs from 1 day old newborns of Control and BPA treated dams. • Culture media - complete medium Analysis • Immunostaining of 10 micron sections: • Nestin – NSC marker • Hes1 - proliferative factor
  20. 20. NSC Immunostaining: 1 Day Newborn Control BPA DAPI (nuclear) + Hes1 (Prolif) DAPI (nuclear) + Nestin (NSC) Cultured for 7 days in complete medium; 10 micron sections
  21. 21. Methods: In Vitro BPA Exposure BPA Treatment of Neural Stem Cells • Hypothalamic NSCs: 1 day old newborns • BPA treatment: • Neurospheres Cultures: Self renewal or differentiated • Dose - 1, 10, 20 mM x 5 days Analysis • MTT assay: NSC proliferation • Protein expression (Western Blot): • Nestin – NSC marker • Hes1 - proliferative factor • Tuj1 - neuronal marker • GFAP - astrocyte • Mash1 - neurogenic factor
  22. 22. BPA: Neural Stem Cell Proliferation BPA (mM) 0 1 10 20 Proliferation Index 0.0 0.1 0.2 0.3 * * BPA 0mM BPA 10mM Increased Proliferation MTT
  23. 23. BPA: Neural Stem Cell Proliferation Factors Control Nestin Hes1 % of Control 0 50 100 150 200 250 * * Increased Proliferative Potential
  24. 24. BPA: Neural Stem Cell Differentiation Increased Neuron to Astrocyte Ratio Control Tuj1/GFAP Mash1 % of Control 0 40 80 120 160 * * Ratio
  25. 25. Programmed Adipogenesis •Adipose Proliferation and Differentiation •Lipogenesis
  26. 26. C/EBPβ C/EBPδ PPARγ RXRα C/EBPα Adipogenic Growth factors SREBP1 ligand Adipogenesis Lipogenesis Regulation of Adipogenesis Peroxisome proliferator-activated receptor gamma 2 (PPARγ2) Nucleus
  27. 27. In Utero BPA Exposure Control and BPA treated dams: 3 week old offspring Retroperitoneal adipose tissue Analysis • Protein Expression (Western Blot): • PPARg – adipogenic transcription factor • C/EBPa – adipogenic transcription factor • SREBP1 – lipogenic transcription factor
  28. 28. BPA: Adipocyte Transcription Factors C/EBPalpha Control BPA Fold change 0.0 0.5 1.0 1.5 2.0 * Control BPA Fold change 0.0 0.5 1.0 1.5 2.0 * Control BPA Fold change 0.0 0.5 1.0 1.5 2.0 * Adipogenic Lipogenic Increased Adipocyte Differentiation and Lipogenesis C/EBPa PPARg SREBP1
  29. 29. Methods: In Vitro BPA Exposure Adipocytes • Subcutaneous adipose tissue: 1 day old newborns • Cultures: pre-adipocytes or differentiated adipocytes • BPA treatment: • Dose - 1, 10, 20 mM • Period of treatment - 5 days Analysis • MTT assay: Preadipocyte proliferation • Oil O Red stain: Preadipocyte lipid storage • Protein expression (Western Blot): • PPARg – adipogenic transcription factor • C/EBPa – adipogenic transcription factor • SREBP1 – lipogenic transcription factor
  30. 30. BPA: Preadipocytes Control BPA (10mg) BPA (mM) Proliferative Index 0.0 0.2 0.4 0.6 0.8 0 1 10 20 * * * Adipogenesis Lipogenesis Increased Proliferation and Lipid Storage
  31. 31. BPA: Differentiated Adipocytes Transcription Factors Fold Change 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 * * BPA (mM) 0 1 10 20 PPARg Fold Change 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 * * * BPA (mM) 0 1 10 20 C/EBPa Adipogenic Fold Change 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 * * * BPA (mM) 0 1 10 20 SREBP1c Lipogenic Increased Adipocyte Differentiation and Lipogenesis
  32. 32. Fetal Programming of Obesity: Effect of BPA Appetite Fetal BPA Exposure
  33. 33. Conclusions •In utero exposures altered nutrition and/or environmental agents may have marked effect on children and grandchildren •Need to refocus environmental agent effects beyond toxicity •Animal studies to explore mechanisms •Correlation of animal and human effects •Longer term human studies •In the meantime, “all things in moderation”

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