Q&A: Impact of endocrine-disrupting chemicals on reproduction, pregnancy

Key takeaways :

• Endocrine-disrupting chemicals have adverse effects on both male and female reproduction.
• Critical effects of EDC exposure occur in utero and during early postnatal development.

Endocrine-disrupting chemicals have clear adverse effects on reproduction, pregnancy and fetal development in animal models. Despite difficulties in studying these chemicals in humans, experts warn that their effects are serious.

One expert, Patricia Hunt, PhD, Regents Professor in the School of Molecular Biosciences at Washington State University in Pullman, was recently awarded the Richard B. Johnson Jr., MD, Prize in Developmental Biology by March of Dimes for her lifetime research on how prenatal development is affected by aging, mistakes in cell division and environmental exposure. The award carries $150,000 and is part of the March of Dimes’ research strategy to address the multi-faceted nature of the maternal and child health crisis. To date, six recipients have gone on to win the Nobel Prize in Physiology or Medicine.

During one investigation of pregnancy loss due to chromosome abnormalities, Hunt and colleagues noted that mice unintentionally exposed to plastics containing bisphenols in caging materials had identifiable chromosomal damage. That experience led Hunt to explore the effects of endocrine-disrupting chemicals (EDCs).

Healio spoke with Hunt about her current focus on effects of exposure to bisphenols and chemicals with estrogenic activity during different time points in reproduction and development.

Healio: What led you to study effects of endocrine-disrupting chemicals on reproduction and pregnancy outcomes?

Hunt: This was a pure accident. We were in the middle of studies trying to understand what goes on with advancing maternal age that causes an increase in chromosomally abnormal eggs. We were using mice as models, and we were getting some good results. We were getting excited about the hypothesis we were testing, and then all of my controls started to show these abnormalities that would lead to chromosomally abnormal eggs. It took us a long time to figure it out, but our animals were inadvertently exposed to bisphenol A (BPA), and we could see it as a dramatic and sudden change in the eggs from control females.

Healio: Could you summarize the effects of bisphenols on mammalian reproduction and then specifically on human reproduction?

Hunt: Our work started with mice and looking at the periovulatory oocyte and seeing an increase in chromosomally abnormal eggs with exposure during the final stages of oocyte growth. We started to look at the very earliest stages of egg development that occur in the fetal ovary, and we saw some striking changes there. That effect, to me, was even more dramatic because a brief exposure to the mother at the right time of pregnancy, when all the oocytes are starting their developmental journey, led to some subtle changes in the early events of egg development. When we let those exposed females grow up, we saw a dramatic increase in the incidence of chromosomally abnormal eggs. We found ourselves with two different ways of making chromosomally abnormal eggs with brief exposures at different developmental stages.

We found some interesting changes in the male as well. There has been a lot of interest in declining sperm counts. The effect we stumbled on in males gave us one mechanism for why we might be seeing decreasing sperm counts. We had different pieces of evidence suggesting that both males and females are vulnerable to the effects of a certain chemical, BPA.

We looked at other types of endocrine-disrupting chemicals and other bisphenols and found similar changes. We did some studies with the rhesus monkey and found that species was also affected. And we have a colleague who works on the worm Caenorhabditis elegans who found the same kinds of effects on oogenesis. We became very concerned.

I had other colleagues who were starting to look at different aspects of fetal development — the developing brain, developing heart, developing lungs, developing reproductive tract — and they were finding effects as well. This raised a lot of concerns about the effects of these chemicals because we’re all exposed to a wide range of these chemicals daily. This has grown to the point where I now look at these endocrine-disrupting chemicals as a global health problem that we need to be concerned about.

Translating this to humans is always tricky. There are several studies in the assisted reproduction field where people have looked at levels of BPA in follicular fluid and found correlations with poor oocyte quality and development with higher levels of this chemical.

It’s important to really realize that BPA is one among a host of other chemicals. It’s the one we know the best because it has received the most attention, but there are a lot of others and trying to link these effects to humans is a major challenge. When I look at the data we have, we can see the same effect if we look at the mouse, if we look at the monkey and if we look at C. elegans, then it’s hard for me to even imagine that humans would not be affected. We’ve been trying for a number of years to do studies to ask this question directly in the human, but it’s going to take time because we started out simply interested in BPA and rapidly realized that we need a much broader exposure profile to look at what a mother’s exposure is doing to the developing fetus. It’s going to take some time, but hopefully we’ll get some direct insight.

Healio: What studies are currently out there on the effects of EDCs on human reproduction and what research is needed?

Hunt: I don’t think we can pin adverse effects to one chemical, simply because we’re exposed to a constellation of chemicals. Studies have found a continual decline in the past 4 or 5 decades in sperm counts, which is troubling. At the same time, we would expect other sorts of abnormalities to pop up in males — that would be things like undescended testes and hypospadias — and you would expect hotspots where there are higher levels of exposure Those sorts of studies are things epidemiologists focus on.

In my world in female reproduction, we’re interested in infertility and whether it has increased or not. A lot of people are seeking help for their fertility issues, but there is growing evidence from experimental studies and from some of these epidemiological studies that exposure to these endocrine disrupting chemicals can be associated with things like polycystic ovary syndrome, endometriosis and fibroid development. There is a lot of reason for concern, but establishing cause and effect in the human is nearly impossible.

Healio: Where can women encounter these chemicals and how can they avoid contact?

Hunt: This is a good question because bisphenols are best known for their use in plastics like polycarbonate. BPA-free plastic products made a lot of consumers think that they were buying safer products when, in fact, manufacturers replaced BPA with other bisphenols. We can’t test all of those as thoroughly as BPA has been tested, but the available information suggests that many are as bad as, and some may be even worse than, BPA. Phthalates are another class of chemicals we use in plastics, and parabens are in our personal care products as an antimicrobial. Then there are a lot of persistent chemicals, like polychlorinated biphenyls (PCBs), dioxins, and pesticides and herbicides that people are familiar with. We’re exposed to them daily.

We can reduce our exposure by using fewer plastics and treating our plastics differently. I always tell consumers that we tend to think of these as long-lasting products, but once these products start showing signs of wear and tear, they’re leaching chemicals. We must consider them not as long-lived products, but products we must replace. We also shouldn’t be putting these things into the dishwasher or in the microwave because heat and detergents are an invitation for chemicals to leach from these products.

If you can afford it, buying organic produce is a way one way to reduce exposure to pesticides. But this is a growing problem, and one of the reasons I never hesitate to talk to someone about this is because I think increasing consumer awareness is an important part of the solution. We really need to help consumers understand what they should be asking for.

Healio: Can you summarize current legislative or social efforts to limit EDCs?

Hunt: This is our most vulnerable spot: The way we have designed tests for chemicals, and whether they are hazardous or not, is based on outdated assumptions that do not hold for these chemicals. It’s really a dilemma because we started off with toxicologists looking at chemicals and asking, Do they mutate our DNA? Do they cause cancer? And in the case of these chemicals, the assumptions made for chemical mutagens, that is, that we should see a dose response — the more we are exposed to, the worse the effect gets — simply don’t apply. Well, these chemicals behave like hormones, and hormones exert powerful effects at extremely low levels, and sometimes when you increase the levels, the effects are not seen. To an endocrinologist who thinks about receptors and how hormones work, this is not surprising, but it sort of defies what we have used as the paradigm in toxicology. The dose makes the poison, the more you’re exposed to, the worse it is. I think it’s been begging us for several decades to reform the way we test chemicals, but we haven’t made those reforms yet.

For BPA, the European Union is really taking a serious look at this and trying to understand whether they should lower the daily tolerable exposure levels for this chemical by 100,000-fold. That’s incredibly dramatic. They are slightly tighter than we are now in terms of what they consider safe daily exposure levels, but this would effectively reduce safe exposure levels to the point where we should not be exposed to these chemicals at all. A lot of us who study these chemicals think that no amount of exposure is safe. These chemicals behave like hormones, and they have no business in our lives.

Making that reform to our regulatory system is going to take some time, and it is going to take some pressure. We are up against huge industries that manufacture these types of chemicals, not just the plastics, but the flame-retardant chemicals and the pesticides and herbicides. These companies have large voice,s and resisting regulatory changes is critical to them. Because, essentially, if we were to tighten regulations and test chemicals the way we really should be testing them, we wouldn’t be able to use many of the chemicals in use today.

Healio: Is there anything else you would like to add?

Hunt: The most vulnerable time for exposure is when we are in utero and shortly thereafter, when we’re developing during postnatal life. There is growing realization that the maternal environment shapes the developing fetus and that exposures during this time are particularly critical. It’s not that exposures to you and I aren’t critical or aren’t bad, it’s just that the effects can be temporary or less severe. Our organs are formed, our brains are developed, but during fetal development, all these tissues are developing. Experimental studies suggest exposures can induce subtle changes in the developing brain, the developing reproductive tract, the developing testis or ovary, heart, lungs, etc, and our immune system that can result in significant effects when that exposed individual becomes an adult.

We not only need to think of our maternal environment in terms of whether our mother has obesity or diabetes or is starving, for example, but how exposed are we during fetal development.

One of the problems with these chemicals is that the most exposed segment of our population tends to be lower socioeconomic groups. Those of us who can afford to live in certain places and buy certain types of food are less exposed than people who can’t afford those things. There is inequity here in terms of exposure, but there is also significant risk to the developing fetus and newborns.

For more information:

Patricia Hunt, PhD, can be reached at pathunt@wsu.edu.