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

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. 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. EDCs on cardiovascular function
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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. 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. 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. 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. Experimental Design
Prenatal Testosterone Study
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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
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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. Results from Testosterone Study
• Blood pressure
• Plasma electrolytes
• Plasma catecholamines

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. 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. 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. 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. 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. Results from BPA Study

15. Prenatal BPA and postnatal overfeeding on blood pressure

16. Prenatal BPA and postnatal overfeeding on interventricular septal
thickness

17. Prenatal BPA and postnatal overfeeding on left ventricular area

18. Prenatal BPA and postnatal overfeeding on end systolic and
diastolic volumes
End Diastolic Volume (ml)

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. 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. Possible Mechanisms

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