This document summarizes a study on the effects of prenatal exposure to bisphenol-A (BPA) and postnatal overfeeding on cardiovascular function in sheep. The study found that overfeeding increased blood pressure but prenatal BPA exposure prevented this effect. Prenatal BPA exposure also increased left ventricular area similarly to postnatal overfeeding. However, the impact of increased left ventricular area from prenatal BPA exposure is unclear. The study suggests that further research is needed to fully examine the cardiovascular effects of prenatal BPA exposure.

1. 2nd GRF One Health Summit 2013
17-20 November, 2013, Davos, Switzerland
Prenatal Exposure to Bisphenol-A and
Postnatal overfeeding on cardiovascular
function in a sheep model
P.S. MohanKumar, A. Veiga-Lopez, V. Padmanabhan,
S. M. MohanKumar
Wed 1.1: Disease Detection and Prevention Technologies
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. Bisphenol-A (BPA)
• Widely used in the synthesis of
plastics
• Prevalent in the environment
• Weak estrogen
• Widespread exposure to BPA –
biomonitoring studies in tissue,
circulation and urine
(Vandernberg et al.,
Environ Health Perspect. 2010
Aug;118(8):1055-1070)

4. BPA 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)

5. 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).

6. Prenatal BPA and postnatal overfeeding: Effects on
cardiovascular function
• Does prenatal exposure to BPA affect
cardiovascular function?
• Whether postnatal overfeeding amplifies
the effects of prenatal BPA exposure on
cardiovascular function?

7. Hypothesis
Prenatal BPA exposure in combination with
postnatal
overfeeding
would
produce
alterations in cardiovascular function resulting
in hypertension.

8. Experimental Design
• 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 groupOF group). The remaining were fed a normal diet (Normal fed-NF
group).
• The cardiovascular function of adult females was assessed using
non-invasive echocardiography at 21 months of age.
• Blood pressure was measured using the tail cuff method.

9. Methods
• Animals were sedated with low dose of Xylazine and Ketamine
and placed in right lateral recumbency.
• An ultrasound transducer probe of appropriate frequency (4 or 5S)
was placed on the 4 or 5th inter-costal space to examine the heart.
• Multiple parameters related to heart functions were determined
using echo.
• Changes in these parameters were analyzed using two-way
ANOVA followed by Fisher’s LSD test.

10. Prenatal BPA and postnatal overfeeding on heart rate

11. Prenatal BPA and postnatal overfeeding on blood pressure

12. Prenatal BPA and postnatal overfeeding on interventricular septal
thickness

13. Prenatal BPA and postnatal overfeeding on left atrial diameter

14. Prenatal BPA and postnatal overfeeding on left ventricular area

15. Prenatal BPA and postnatal overfeeding on interventricular
septal thickness

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

17. 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.

18. Conclusions
 Prenatal BPA exposure decreases overfeeding-induced
hypertension, contrary to our expectations.
 The impact of prenatal BPA exposure-induced increase
in left ventricular area during systole is unclear.
 Further studies are needed to systematically examine
the cardiovascular effects of prenatal BPA exposure.

19. Disease Detection and Prevention Strategies
• Detection
– Already available techniques
• Conventional cardiovascular monitoring
– BP monitoring, Echo
– Detection of marker proteins
– New opportunities
• Develop new cost effective biomarker panels
• miRNAs related to cardiovascular function
• Prevention
– Education
– Reduce, Reuse, Recycle
– Neutralize

20. Acknowledgements
University of Michigan
• Dr. Vasantha Padmanabhan
• Dr. Almudena Veiga
Students
•Natalie Baca
•Dr. Ninitha Asirvatham Jeyaraj
Michigan State University
• Dr. Gregory Fink
• Dr. Bari Olivier
• Dr. A. Pease
• Dr. F. Garcia
• Dr. Arpita Vyas
Funding
•NIH (R01ES016541)
•USDA – Michigan AgBio
Research