Prenatal Exposure to EDCs and its Effects on the Cardiovascular Function in Adulthoodar

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GRF 2nd One Health Summit 2013: Presentation by MOHANKUMAR, Dr. P. S, Michigan State University

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Prenatal Exposure to EDCs and its Effects on the Cardiovascular Function in Adulthoodar

  1. 1. 2nd GRF One Health Summit 2013 17-20 November, 2013, Davos, Switzerland Prenatal Exposure to EDCs and its Effects on the Cardiovascular Function in Adulthood P.S. MohanKumar. V. Padmanabhan and S. M. MohanKumar Wed 5.1: Prenatal Exposure to Endocrine Disruptors And its Impact on Adult Onset Disorders College of Veterinary Medicine Michigan State University
  2. 2. Prevention, Detection/Diagnosis and Treatment • Cardiovascular diseases  Leading cause of death all over the world  Cause huge economic loss  Multivariate causes • Prevention and early detection will help treatment and reduce mortality
  3. 3. EDCs on cardiovascular function • • • • • Higher urinary concentrations of BPA is associated with heart disease (Melzer et al., 2010) Higher urinary concentrations of BPA is associated with coronary artery disease (Melzer et al., Circulation 125: 1482-1490, 2012) Higher urinary concentrations of BPA is associated with obesity in children and adolescents [Trasende et al., JAMA. 2012 Sep 19;308(11):1113-21] Urinary BPA levels are significantly associated with peripheral arterial disease [Shankar et al., Environ Health Perspect. 2012 September; 120(9): 1297–1300] Urinary BPA levels are associated with hypertension (Shankar and Teppala, J Environ Public Health. 2012)
  4. 4. Endocrine manipulations and cardiovascular function • Prenatal androgen programming causes hypertension in female offspring – sheep model – King et al., 2009 Am J Physiol 292: E1837E1841 • Exposure to low levels of estradiol-17beta (20 ng/day) for a prolonged period of time (90 days) causes hypertension in rats – reversal by antioxidants – (Subramanian et al., 2011 – Am J Physiol 300: R1560-R1568).
  5. 5. Core Hypothesis Exposure to excess native or environmental sex steroids during critical periods of development produces changes in postnatal cardiovascular dysfunctions in adult life.
  6. 6. Prenatal T & Prenatal BPA and postnatal overfeeding: Effects on cardiovascular function • Does prenatal exposure to either T or BPA affect cardiovascular function? • Whether postnatal overfeeding amplifies the effects of prenatal BPA exposure on cardiovascular function?
  7. 7. Experimental Design Prenatal Testosterone Study • • • • • Pregnant sheep were given daily subcutaneous injections of cottonseed oil (control) or Testosterone proprionate (100 mg, I/M, twice weekly) from day 30 to 90 of gestation. A subset of 2-yr old female offspring of these dams were ovariectomized, clampled with early follicular phase levels of estradiol by implants. Implanted with telemeters to monitor cardiovascular function. Plsma lipids and electroylytes were measured. Sympathetic activity was assessed by measuring plasma catecholmaines Prenatal BPA study • • • • Pregnant sheep were given daily subcutaneous injections of cottonseed oil (control) or BPA (0.5 mg/kg/day in cotton seed oil) from day 30 to 90 of gestation. A subset of female offspring of these dams were overfed to increase bodyweight to ~30% over that of controls (overfed group-OF group). The remaining were fed a normal diet (Normal fed-NF group). The cardiovascular function of adult females was assessed using noninvasive echocardiography at 21 months of age. Blood pressure was measured using cuff method.
  8. 8. Results from Testosterone Study • Blood pressure • Plasma electrolytes • Plasma catecholamines
  9. 9. Effects of Prenatal T on cardiovascular function in adulthood One-hour mean arterial pressure (A) and heart rate (B) averages for the 24-h recording period in control and prenatal testosterone-treated (T-treated) female sheep. *P < 0.05, 24-h average compared with control sheep. King A J et al. Am J Physiol Endocrinol Metab 2007;292:E1837-E1841
  10. 10. Effects of Prenatal T on cardiovascular function in adulthood Twenty-four-hour averages of physiological parameters measured by radiotelemetry in prenatal Ttreated and control sheep Group MAP, mmHg Control 90.9±2.8 T treated 100.5±2.7* SBP, mmHg 115.1±4.5 125.0±2.8 DBP, mmHg PP, mmHg HR, beats/min 79.2±2.3 88.9±2.8* 35.9±3 35.9±0.3 73.5±5.9 82.5±7.4 Values are means ± SE. T treated, prenatal testosterone treated; MAP, mean arterial pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; PP, pulse pressure; HR, heart rate. * P < 0.05, prenatal T-treated group compared with control group.
  11. 11. Effects of Prenatal T on Plasma Aldosterone and Plasma Catecholamines Plasma aldosterone (A), norepinephrine (B), and epinephrine (C) in control and prenatal T-treated sheep. *P < 0.05 compared with control sheep. King A J et al. Am J Physiol Endocrinol Metab 2007;292:E1837-E1841
  12. 12. Effects of Prenatal T on postnatal plasma electrolytes and glucose Group Na+, mmol/l K+, mmol/l Cl−, mmol/l Glucose, mg/dl Control 138.8±3.3 4.4±0.1 108.3±2.2 59.5±1.8 T treated 149.5±2.1* 4.4±0.3 114.5±1.3* 66.8±1.8* No change in lipid profiles Values are means ± SE. * P < 0.05 prenatal T-treated group compared with control group.
  13. 13. Summary T study • Elevates Diastolic and Mean Arterial Blood pressure • Elevates Na, Cl and glucose, - No changes in lipids • Decreases plasma aldosterone • Decreases plasma norepinephrine
  14. 14. Results from BPA Study
  15. 15. Prenatal BPA and postnatal overfeeding on blood pressure
  16. 16. Prenatal BPA and postnatal overfeeding on interventricular septal thickness
  17. 17. Prenatal BPA and postnatal overfeeding on left ventricular area
  18. 18. Prenatal BPA and postnatal overfeeding on end systolic and diastolic volumes End Diastolic Volume (ml)
  19. 19. Summary Overfeeding produced a reduction in heart rate and increase in blood pressure. Prenatal BPA treatment prevented overfeeding-induced increase in blood pressure. Prenatal BPA exposure increased left ventricular area during systole similar to postnatal overfeeding.
  20. 20. Conclusions  Prenatal programming with Endocrine Disrupting Chemicals affects cardiovascular function in offspring during adult life.  Further studies are needed to systematically examine the cardiovascular effects of EDCs  Provides insights into possible strategies for prevention and treatment of EDC-induced changes.
  21. 21. Possible Mechanisms
  22. 22. Acknowledgements University of Michigan • Dr. Vasantha Padmanabhan • Dr. Almudena Veiga Michigan State University • Dr. Gregory Fink • Dr. Bari Olivier • Dr. A. Pease • Dr. F. Garcia • Dr. Arpita Vyas Students •Natalie Baca •Dr. Ninitha Asirvatham Jeyaraj Funding •NIH (R01ES016541) •USDA – Michigan AgBio Research •Vice President for Research, MSU •CVM, IIH - MSU

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