Prenatal Exposure to Mixtures of Endocrine Disrupting Chemicals and its Repercussions in Adult Life


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

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  • Good afternoon everyone. Thank you for the opportunity. I am going to continue on the theme of endocrine disruptors and focus on the prenatal exposures to mixtures of EDCs.
  • BPA as mentioned earlier is a plasticizing agent. Millions of pounds of BPA are produced every year in the US alone. Developing countries do not have proper regulations to dispose plastics. Recycling is not implemented seriously. People frequently burn plastics, or dispose them with garbage leading to atmospheric and ground water pollution with this endocrine disruptor.
  • The other EDC that we will be discussing today is DEHP. A large amount of DEHP is produced around the world and people are inadvertently exposed to this chemical as well. However, unlike BPA that has been linked to reproductive disorders and metabolic syndrome, the effects of DEHP have not been studied in great detail.
  • Exposure to these EDCs is a serious One health issue. In developing nations, where disposal of plastics is not well regulated, we have cows and sheep grazing on these plastics. This gives them indigestion, but since they are broken down to a certain extent in the rumen, there are greater chances for EDCs to be liberated and enter the circulation contaminating meat and milk. Although humans are exposed to BPA and DEHP through several routes, consumption of contaminated meat and milk is another potential mode of exposure. Therefore, it is important to understand the mechanisms by which EDC exposure can cause non-communicable diseases in humans and also pets. The talks in this session will explore the effects of BPA on reproductive and cardiovascular functions, the effects of a mixture of BPA and DEHP on body functions and investigate the use of stem cells to screen for the presence of EDCs. Our first speaker, Dr. Vasantha Padmanabhan from the University of Michigan could not be here, but Dr. P.S. MohanKumar will be presenting her talk instead.
  • Humans and animals are more commonly exposed to mixtures of EDCs than any one single EDC. In our studies, we have used a combination of BPA and DEHP. Previous studies have shown that adult exposures to BPA can produce reproductive effects such as reduced luteinizing hormone secretion and PCOS. It has also been associated with metabolic disorders such as obesity and as seen in the previous talk-with cardiovascular dysfunction as well. In contrast to BPA, the effects of DEHP exposures have not been studied extensively. It is known to inhibit spermatogenesis mainly by acting through Aryl hydrocarbon receptors and PPAR alpha. It is also known to affect the immune system and decrease IFN alpha production.
  • We hypothesized that prenatal exposures to EDCs and their mixtures can cause intra-uterine growth retardation and/or program the fetus. This could lead to adult onset disorders such as obesity, diabetes, and hypertension.
  • To test our hypothesis, we used adult female Sprague Dawley rats, bred them and when they were pregnant, started treating them with BPA or DEHP or a combination of BPA and DEHP through oral gavage from day 6-21 of gestation. When the offspring were born, we measured their birth weight, head circumference, ano-genital distance etc. We also monitored estrous cyclicity in female offspring by vaginal cytology. A few of these animals were implanted with radiotelemeters to measures changes in cardiovascular function.
  • Results showed that prenatal BPA exposure decreased body weight compared to controls. This is likely to set the stage for postnatal “catch-up growth” that is well established to cause adult disorders. We did not see this effect with DEHP exposure alone, or when the offspring were exposed to mixtures of BPA and DEHP. The head circumference in the offspring were significantly reduced when animals were prenatally exposed to BPA and DEHP individually and in combination.
  • Female rats exhibit 4-5 day estrous cycles. Vaginal cytology is monitored for 2 weeks and the smears are examined under a microscope to determine if they have regular cycles or have irregular cycles. This graph shows that about 85% of control rats have regular cycles, offspring prenatally exposed to BPA shows a reduction in regular cycles, there is a more marked reduction in regular cycles with D exposure alone, and the combination of BPA and DEHP appears to have an effect comparable to that of BPA alone. This indicates that prenatal exposure to these EDCs interferes with reproductive function. In the next couple of slides, I will show you the effects of these exposures on cardiovascular function.
  • We did not see any change in systolic or diastolic blood pressure
  • But we did see an reduction in pulse pressure in animals exposed to BPA and an increase in heart rate in animals exposed to DEHP alone. The combination does not appear to affect either of these parameters. This study is still ongoing as I speak, we have two weeks worth of data, but the telemeters will remain in these animals for another 2.5 months and we will continue to follow changes in cardiovascular function.
  • Results from our studies show that prenatal exposures to EDCs affects birth weight and individual EDCs and their mixtures can decrease head circumference. EDCs and mixtures can also affect heart function. There is a need to study the underlying possibly “programming effects” that include epigenetic mechanisms. We also need to study the effects on metabolic disorders.
  • Prenatal Exposure to Mixtures of Endocrine Disrupting Chemicals and its Repercussions in Adult Life

    1. 1. Sheba M.J. MohanKumar, Joseph Henriquez, Arthanari Kannan, Kelly Stewart, Rhyomi Sellnow and P.S. MohanKumar Neuroendocrine Research Laboratory, College of Veterinary Medicine, Michigan State University, E. Lansing, MI, USA
    2. 2. EDCs-BPA Bisphenol-A 6 billion pounds around the world 200,000 pounds released into the environment every year Humans are exposed to more than 50μg/kg BW/day
    3. 3. EDCs-DEHP Diethyl hexyl phthalate-DEHP 18 billion pounds around the world Household dust has 400-700mg of DEHP
    4. 4. EDC exposures- relevance to One health Leaching of EDCs from lining of food cans-glucose, sodium chloride content favors leaching Human contact through EDC-coated paper-sales receipts. Animals chew on plastic toys
    5. 5. EDCs – a One health problem Cows grazing on plastic Plastic removed from rumen EDCs in milk/meat? Human exposures
    6. 6. EDC mixtures Exposure to mixtures are more common than individual exposures Our studies used a combination of BPA and DEHP BPA Reproductive effects Metabolic disorders-obesity Cardiovascular dysfunction DEHP Very little is known. Inhibit spermatogenesis- effect likely mediated through PPAR alpha  Decreases interferon alpha 
    7. 7. Prenatal exposures to EDC mixtures Hypothesis: Prenatal exposure to EDCs ? ? Intrauterine growth Retardation Programing of the fetus Adult onset disorders
    8. 8. Approach: • Adult female Sprague Dawley rats, bred • BPA 5 μg/kg BW, DEHP 7.5 mg/kg BW or BPA+DEHP given by oral gavage- day 6-21 of gestation • Morphometric measures- birth weight etc. • Cyclicity in female offspring were measured by vaginal cytology • Implanted with radio-telemeters to measure blood pressure
    9. 9. 9 Weight (g) 8 * 7 6 5 4 3 Control BPA DEHP BPA-DEHP Treatment Head circumference (mm) Birth weight and head circumference 42 41 40 * 39 38 37 * * 36 35 Control BPA DEHP BPA-DEHP Treatment
    10. 10. Adult disorders- Irregularity of reproductive cycles Regular Irregular 80 60 40 20 Treatment Groups B +D D EH P B PA on tr ol 0 C Percentage of animals 100
    11. 11. tr ol D EH P B PA on Treatment groups B PA +D EH P D EH P B PA ol 0 tr 50 on 100 Diastolic pressure (mmHg) 150 C B PA +D EH P C Systolic Pressure (mm Hg) Changes in cardiovascular function 150 100 50 0 Treatment groups
    12. 12. tr ol D EH P Treatment groups BP A+ HP HP A 450 DE DE BP 0 ol 10 tr 20 on 30 Heart rate (beats/min) * C 40 B PA on 50 B PA +D EH P C Pulse Pressure (mm Hg) Cardiovascular function ctd.. * 400 350 300 Treatment groups
    13. 13. Summary and conclusions: • • • • • Prenatal exposures to EDCs affects birth weight EDCs and mixtures decrease head circumference EDCs and mixtures affect cardiovascular function Changes in epigenetic mechanisms need to be studied Effects on metabolic disorders need to be investigated
    14. 14. Preventing EDC-induced adult disorders • Limit exposures- strategies for regulating disposal and usage. • Stabilize plastics-prevent leaching. • Conduct detailed studies on developmental effects-prenatal and postnatal before using new chemicals in manufacture. • Public awareness- early detection of disorders
    15. 15. Acknowledgement • Dr. Gregory Fink, MSU • Hannah Garver • MSU AgBioresearch • CVM-MSU