The Connection Between the Womb and Lifelong Health: Conversation with Dr. Alison Paquette

What happens in the womb doesn't stay in the womb--so said David Barker in the 1990s, a British epidemiologist, ​Barker found associations between birth weight and the likelihood of developing cardiovascular disease later in life.​  He argued that the uterine environment can have long term effects on future health.  Much work has been done to map out exactly how ​fetal experience during pregnancy translates to someone's health trajectory.​ Today's guest is using omics data and placental samples to more clearly trace out how exposures in pregnancy can impact fetal development and long term health .  

To see some of Dr. Paquette's work: https://www.seattlechildrens.org/directory/alison-paquette/

Intergenerational Transmission of Environmental Exposures, Michael Skinner: https://www.youtube.com/watch?v=f1Pf5S8Nbfk

Transcript

[00:00:00] What happens in the womb doesn't stay in the womb, so said David Barker in the 1990s. A British epidemiologist, Barker found associations between birth weight and the likelihood of developing cardiovascular disease later in life. He argued that the uterine environment can have long term effects on future health.

Much work has been done to map out exactly how fetal experience during pregnancy translates to someone's health trajectory. Today's guest is using omics data and placental samples to more clearly trace out how exposures in pregnancy can impact fetal development and long term health. Welcome to Making Sense of Pregnancy.

This show is a new pregnancy reference. I'm finding and talking with experts doing cutting edge work to better understand what we do and don't know about pregnancy and what you can do to better understand your own [00:01:00] experience. Each week, I'll be talking to scientists, doctors, and researchers who are trying to uncover the many mysteries that still exist in reproduction, giving you the most current, evidence based way to approach this enormous transition in your life.

I hope it will become your go to source for how to make your pregnancy better. Please enjoy my conversation with Dr. Allison Paquette.

Today, we're lucky to have Dr. Allison Paquette on the show. She's an assistant professor in the Center for Developmental Biology and 

And 

medicine in Seattle Children's Research Institute, focusing on using omics data from the placenta to understand the developmental origins of health and disease.   

Dr. Parkett, thanks so much for coming on the show.

Thank you so much for having me. I'm really excited to be here. 

 So I'm excited to get into this, and I thought first I would have you describe both omics data, what that means and how you're using it to investigate the health [00:02:00] of the placenta , and why you're doing that.

Yes. Yeah. I would be happy to elaborate on those. So omics data is another way of saying molecular data in the placenta. And I listened to Mana Paras, amazing podcast. I'm a big fan of her work. And she talked about placental pathology and more, global things that you can look at with the eye, right?

You can see , oh, the placenta is calcified. , you could look under a microscope and see some of these molecular changes. But what omics data is referring to is very small molecular changes. So, omics data is a very broad category, and the most well known omics data is genomic data.

 What is your genotype? When you take 23andMe, you have your genes. And your DNA encodes RNA, which is translated to protein, which is the building blocks of the cell going back to basic biology. But in the last 20 years, we've been able to expand this and we can 

[00:03:00] Look at many different other types of data.

We can look at the RNA, which is, what is actually expressed in the cell. And then there's the proteins, which are, what the RNA has been translated into. And then there's many, many other types of omics data, such as epigenomic data, which is a marker of gene expression potential.

And we're discovering new types of omics data all the time. There's an emerging field of epitranscriptomics data. And so it's scaling out, , there's metabolomics data, which is the end results of all these biological processes. So they're molecular measurements of what is occurring in an organ at a given time.

And so I look at omics data in the placenta. 

 So that sounds amazing. And the way I think about it is that DNA is the menu and RNA is what's actually ordered, even though there are all different kinds of RNA. , 

but so you're figuring out what the cells are actually producing. 

Yeah, exactly.

 That's kind of what I say so your DNA is. , what is written down what could [00:04:00] possibly happen epigenomics data is, what has the potential to happen in a given cell type because everything is different and then transcriptomics data is sort of what is happening.

 At a given time point. And so, there's many different omics data we can generate. And I'm really interested in how we can put that data together to learn. More. And I think omics data really lends itself to this precision medicine approach, which has become very popular recently in science, which is taking all of these molecular data and asking, what is unique about every individual on a molecular level that affects how they respond to a given situation and how different pathophysiologies occur.

 It seems amazing to me because instead of 

Looking at what I'd call macro data. 

, oh, you're a woman between 20 and 30. And so we'll give you this drug. This is so much more precise to say this is what's actually going on in your body And this is why this drug may or may not work [00:05:00] 

yeah, exactly.

And it's been used so much for cancer research An example is breast cancer. We didn't know previously that there are all these different molecular subtypes of breast cancer that are responsive to different drugs. And so we learned that a while ago, but we still don't really have, , insight into what's going on in pregnancy or in the placenta.

So, , there's things that you can see on a global level when you look at a placenta, but there's probably more things that are going on internally that we can't really see. So looking towards how can we generate this data. And take a deeper look, 

 And one thing I found interesting about a lot of your research is that you're looking in particular at the Barker hypothesis aka fetal programming or the developmental origin of health and disease.

It's got all these different names. Yes. Do you want to define for us what that looks like in your lab? 

Yes, I would love to talk about it. so the Barker hypothesis, , it was developed by David Barker the idea of the developmental origins of health and disease hypothesis is that [00:06:00] the short time period of development. Remember, it's only nine months shapes your health throughout the lifespan. And there's been a lot of studies that have occurred. Okay. over the past several years that have shown that things like cardiovascular disease, obesity, all of this stuff can be linked back to changes that happen during gestation.

And so in the early 90s. David Barker was looking at , birth records of people that had been born during various, , events, like the Dutch hunger winter, which happened during World War 2 and found that these people who are much more likely to develop cardiovascular disease later in life.   

So, just to give a little more detail here, the Nazis cut off food supplies to the Netherlands at the end of World War II, which led to what's called the Dutch Hunger Winter. Women who were pregnant during this famine suffered from malnutrition, and gave birth to babies that were [00:07:00] relatively small. And for the babies, exposure to that circumstance in the womb affected their health trajectory later in life.

So that's the big picture theory. , a lot of my work, especially with the omics data has centered around. , What happens during development and childhood outcomes because, it takes a long time to see these long term health outcomes. So right now we can really only follow them in children. 

 When I first heard the hypothesis, I thought this can't possibly be right. . And then once you really think about it, it makes perfect sense that the uterine environment in which all these organs are being developed will shape those organs in a very particular way.

which of course could have effects as you grow up. So for example, if you don't have enough nutrition, maybe nutrients are going to vital things like the brain and the heart, and they may not be as many nutrients for something like the kidney, and that will affect kidney development. And so if your kidney has fewer nephrons, the little structural bits that do the filtering, you may end up with a kidney problem later in [00:08:00] life.

Yeah, exactly. There's actually some really interesting studies showing that women with preeclampsia the kids can have kidney problems later in life. There's some great work coming out of OHSU. 

 It's also interesting thinking about, nutrition and metabolism because your, your metabolic programming is occurring while you're being developed. And if you're growing up in a nutrient starved environment, do you need to encode programs that are going to make sure that you're storing all these nutrients and that, you're set up.

Or if you're having a lot of nutrients, you're going to grow pretty fast. So, yeah, it's really setting things up for later in life. 

So with examples like preeclampsia or, , gestational diabetes or , gestational hypertension. The case to be made for uterine environment affecting, , fetal development seems, , pretty straightforward in part because you have these markers of specific issues.

But some of your work , takes a deeper dive and looks for exposures, like pollution exposures . So I could easily be exposed to pollution, and it wouldn't be obvious that [00:09:00] there's an effect on the baby, but you're looking at stuff like that, right?

Yeah, exactly. A lot of my work and what I'm really most passionate about is looking at environmental exposures in pregnancy. And I think there's some great examples of this from early work, , that kind of set the stage for the Barker hypothesis. For example, thalidomide, you can think of that as an exposure.

 That was being prescribed in the 1960s for some pregnancy complications like nausea, and there were very experimental effects on these. And so another example is alcohol use during pregnancy. Fetal alcohol syndrome is a very extreme end of the spectrum. And so those are some exposures we know pretty well, but in reality, we're exposed to thousands of different chemicals a day, and some of them have no effect.

Some of them have subclinical effects. And we're just trying to learn, , what of these exposures are the most concerning? 

So, I don't want to freak out any pregnant women who are listening to this. When I was reading through some of your work, I thought, if I were [00:10:00] pregnant, there are certain things I can avoid. 

I can 

avoid alcohol and cigarettes. 

But

there are many things I can't avoid that are just in the environment around me. , is the goal of your work to figure out how those pollutants affect the placenta and potentially affect fetal health so that we can address. The newborn, when they're born, because we know that they've been made in this environment, what do we do in response to this?

Yeah, 

that's a great question. I think a really important part of the work that we talk about is not blaming blaming the mother for anything that's happened during pregnancy, because it's so challenging to avoid these exposures. We need plastics. To, survive.

, these chemicals are in lots of different products. Not only personal care products, but they're in a lot of medical, , products as well. For example, drugs, sometimes the coating can be plastic. They're just in many, many different things. And then there's some exposures in medical settings.

For example, blood bags have a lot of [00:11:00] phthalates and they need to have phthalates because, , the bags need to be soft and bendable. So it's really, really hard to avoid these things. I think really what I think about is prioritizing things there's replacement chemicals that are coming up with.

So, which of these are having less changes. We're having more changes and then also our work can impact policy decisions because I think you need mechanistic evidence. to influence policy. We can't just be like, oh, we found these associations. We need to understand , how are these chemicals actually changing the central physiology.

So I think, working together with toxicologists can really help inform these, these studies. 

 It's super important. And any time I read something like this, I think how do we not know this? And why aren't we taking better care of Pregnant women, it's just civilization. Why isn't this the focus of many more things?

 , I think there is a lot of work that people do on toxicology studies. The EPA, the FDA, they do a lot of [00:12:00] work making sure that these These chemicals are safe, but they can only do it up to a certain point, and some of these effects are maybe more subtle, and you might not be able to pick them up, especially with reproductive toxicity, because the placenta and the immune environment is so specialized to humans.

It's really hard to model. Monoporos talked a little bit about , these challenges with these models, especially in a dynamic environment where things are changing. So an exposure. that can happen during the first trimester might be a big deal while, certain parts of your body are , developing like your neural tube, but an exposure later in pregnancy may not have as much of an effect because that has already been developed.

So it's just a really challenging field to work within. 

 Do you want to talk at all about, , the impact of social stressors on the placenta and fetal development? 

Yeah, absolutely. I can talk a little bit about that. , So we've done a little bit of work on social stress. This is with Brennan [00:13:00] Baker, who is a postdoctoral fellow here at Seattle Children's and there's other studies that have come out looking at more extreme social stressors, but we looked at things like, pre pregnancy stressors, and stress during pregnancy, so things like, social support systems, like did your partner leave you, did you lose your job, did you get laid off, did you lose your house, did a loved one die? So we had this survey of 14 questions during pregnancy to try to assess stress during pregnancy.

And then we also asked about childhood stress. So that's sort of related to maternal programming, and we found a couple of genes, just a handful of genes associated with stress during pregnancy. We didn't really see any associations with, exposures before pregnancy, , during maternal childhood stress, so when mom was growing up.

, and then there's been other studies looking at acute stressful events during pregnancy. So [00:14:00] example, there's a lot of great work coming out of Columbia. And other institutions looking at people who were pregnant during 9 11, which was a really acute event. And there was, a lot of social stress.

And there was also some exposures during that time. And so there's been some transcriptomic studies, and then there's another study where they looked at Superstorm Sandy, which also happened in New York, , and that was an acute stressor, social stressor where people didn't have power, and one of those genes was associated, was also associated with stress in our study. I think it's hard because there's extreme stressors and then there's more subtle things. So I think we need many studies looking at all sorts of things in the spectrum to understand that. I've also done some work, , during my PhD where I was looking at, DNA methylation of cortisol response genes and trying to understand a little bit about cortisol signaling in the placenta.

And it was interesting because we picked this one gene that is it's called FKBP5 and it's most known for post traumatic stress [00:15:00] disorder. And it's a marker of post traumatic stress disorder. But we actually found that It was associated with, the placental ex methylation of this gene was associated with infant health outcomes.

So I think there's a level of cortisol programming that happens during pregnancy that can influence, childhood, development and neurobehavior. And there's a lot of in vitro studies that, have support this, especially some work by Michael Skinner out of, , Washington State University.

So super interesting, , how, malleable, do we think these developmental impacts are once you're out in the world , as a baby? Now that we know about epigenetics, , I'm assuming we're talking about these placental insults in part because Unlike your genes, you can address some of these.

Yeah, exactly. I think there's a lot of interesting work suggesting that these may be malleable. There's a lot of in vitro studies that people, [00:16:00] will have exposure to stressors in animals during pregnancy and see what these epigenetic changes of things are altered and how the long term effects on the infants, but we actually have a study right Sathinyarana, who's here at Seattle Children's with us.

, And we have a study where we've collected placentas from infants, and we're going to look at DNA methylation. And then we have information about exposures, and then we're looking at neurobehavioral outcomes in these kids. And we want to look at potential modifiers, which is, I think, what you're talking about, , are there ways that we could mitigate these stressors?

And so, There's 2 things that we're looking at, and this is also with Brent Collette, who's a psychologist here at Seattle Children's, and we're going to look at interventions with reading and, in that , on neurodevelopment, and then we're also going to look at nutrition.

With the environmental exposure, so is there some evidence that maternal nutrition or childhood nutrition might be able to mitigate some of [00:17:00] the effects on, on molecular level? 

 I just want to point out that all this stuff is going on, whether you're studying it or not.

Your study of it is making us more aware, and hopefully we can address these things, as we learn more about how these systems are working together. Mm hmm. How do you differentiate between, fetal or newborn impacts that are genetic and that are from some change in the way the placenta is, , regulating communication between mom and baby?

Yeah, that's a great question. So that's where multi omics data can come in really handy. Is because if you can look at genetic variance, then you can do subsetting, like, okay, I see this gene expression change in the placenta related to an outcome of interest, and then you could take a step back and be like, are genetic variants associated with it?

And then you could take a step further back in these placentas, Is there a difference in [00:18:00] these genetic in expression based on these two genetic variants. And so with that FKBP5 study, we were able to look at a specific genetic variant and how it affected DNA methylation and gene expression.

But that was one gene. And so this was in 20, 14 2015. And at that point in time, we were doing a lot on gene by gene level. And this is when I was doing my PhD thesis. But now we're starting to get genomics data on all these samples, which really opens the door of what we can do. And so we're recently gonna be able to get genomics data on some of these samples, and that would allow us to do this on a larger scale.

 So that one gene is looking at, , intergenerational transmission of trauma or something like that, right? 

It's doing lots of different things. , I think when you, search it, it's like, these genes are named and initially studied in one context. Okay. But what you'll find is, , they actually do many, many different things, and we [00:19:00] know that this gene.

 It is a chaperone for the glucocorticoid receptor. So it's involved in glucocorticoid signaling. And in adults, that's related to stress response. But in pregnancy, glucocorticoids are doing other roles. So they're important for fetal development and like lung development.

So they're doing sort of different things. 

, that is interesting. So it's a little bit hard to tell how they land. 

Yeah, yeah, exactly. It's an evolving field and I think we're learning a lot. , About just glucocorticoid signaling, but these stress response pathways are actually recently did a study on CRH, which is yeah, 

I saw that 

hormone.

So this was an interesting study because we know in adults, corticotriphin releasing hormone is producing the hypothalamus in response to stress, but a lot of Really important work by Roger Smith, in the 90s revealed that CRH is [00:20:00] actually increasing exponentially in the placenta. So, you can't really measure it in non pregnant individuals in the blood.

But , once you're in your third trimester of pregnancy, it's measured , I think, a thousand times higher than non pregnancy. So, the placenta is producing massive amounts of CRH. And We're trying to understand, , what that CRH does, and I think it plays a very important role in labor initiation. So we were trying to look at changes in the CRH during labor and how they related to, , preterm birth and gestational age.

And we did find some overlapping genes suggesting that CRH was altering , some pathways and some genes involved in gestational length. Like, how long the pregnancy progressed to. And then it was interesting because we overlapped the genes that were associated with CRH with the genes that we found in that other study that were associated with maternal stress.

And we actually, did not see any overlap in those genes, even when we took a looser statistical threshold. So, I think it's showing that whatever CRH is doing is [00:21:00] independent of stress. 

That's interesting, and it does suggest, that CRH has many more jobs in the fetus than it does in the adult.

Yes, exactly. , 

. So two more questions. One is, I want to hear about your work with preterm labor. You're trying to figure out if there are markers of preterm labor in the placenta? 

Yeah, so I've done a couple different studies looking at preterm birth and preterm labor and identifying molecular changes in the placenta.

And some of the work I've done recently has really focused on spontaneous preterm birth, which is important because the preterm birth is a broad category. , there's a number of reasons why someone would be born before 37 weeks. Sometimes individuals with twins, for example, or multi fetal gestations, they're going to be born earlier.

, preeclampsia, you can be born earlier. So we tried to be very careful about developing our data set in a way where we were only looking at spontaneous preterm birth. So we [00:22:00] excluded anyone that was induced because if you had induced labor, you probably weren't spontaneous, right? So we identified many, many gene expression changes, I think we had 917 differentially expressed genes and many, like 60 biological pathways.

And what I'm really interested in doing is finding out which of these genes and which of these pathways are associated with environmental chemicals, because that can show us, from these environmental chemicals, Which of these biological pathways that we see affected are also related to preterm birth and then would like to do some more sophisticated analysis to try to understand causality.

Okay, it sounds like , the spontaneous preterm births that you are looking at, the placenta is somehow getting the wrong message about what time it is in the gestation.

Yeah, exactly. Yeah, it's that, subtype of preterm birth that is, , not for those other reasons, , there's no infection, there's no, evidence of, growth restriction. So, yeah, how do you narrow that down? And that becomes hard because [00:23:00] when you start doing that, you need more and more people in your study to capture that small subset of people with preterm birth, and it's very hard to enroll those people, right?

 If you're coming in at a certain time point, if you're coming in to the delivery room and you're like, oh, I'm giving birth at 35 weeks. You can't be enrolled in a research study at that time. Right? Yeah. So we work with large cohort studies. , and a portion of those people happen to be born preterm.

And we just do the best we can to , understand that subtype.

 If we have the biomarker and , we have evidence that it is going to be a spontaneous preterm birth, , for reasons other than placental malfunction, then maybe we would use these biomarkers to try to turn that off. I'm assuming. 

Yeah, we could do that.

 I think from my perspective, I'm really interested in mechanisms, right? So if we can see what's different about these preterm placentas? And if we can tie these back to environmental chemicals, then we can see , oh, maybe these chemicals are more associated with preterm birth.

Maybe these chemicals are less [00:24:00] associated with preterm birth. And we can understand what mechanisms these chemicals might be related to preterm birth. 

So, I was wondering if there were any surprises from your research. 

Yeah, that's a good question. There's a couple different things. I think the biggest surprise for me recently was with that CRH paper, learning that maternal stress, those genes were independent of the CRH genes.

And then I think as far as the environmental exposure study, I started out working with phthalates, which has been really interesting. And we've published a couple other papers looking at other environmental chemicals. , So we've looked at things like polycyclic aromatic hydrocarbons, which are in unfortunately like when you roast coffee, , it's burned food, when there's, , forest fires, it's in lots of processed food.

Yeah. It's so it's in lots of different things. And we've also looked at some flame retardants. I'm interested in other things, but I think what's surprising to me is we've done the most gene expression changes with phthalates and we've actually found consistent gene expressions. Changes with phthalates, and I [00:25:00] think there's been a lot of studies with phthalates. 

But the signals that we're seeing are the strongest with those chemicals. And in fact, these newer chemicals, these newer replacements, we've seen more changes with some of them. Another thing that's been really interesting is we've seen, more changes in gene expression in boys. So, mothers carrying males, , and male placentas.

They have, we've seen in one study, we saw more gene expression changes in boys, and then we got another, we did another study where we actually, worked with some collaborators at OHSU, and we got placental samples, and we treated the placental samples with specific phthalates, and we, we then measured the gene expression changes, and this is like a little bit more, causative since we had male and female samples because they were derived from pregnancies and the boys still had many more gene expression changes.

So I think it's possible that males are more, at least what we're seeing is that males are having higher gene expression changes in relation to [00:26:00] these chemicals. But there's also this contributes to a larger body of evidence suggesting that male placentas are more susceptible to environmental insults.

That's really interesting and we, do you know when phthalates became so omnipresent? 

Yeah, I think , it's been in the last, hundred years or so as more and more people are using plasticizer products.

It happens gradually over time. There's been a lot of changes to the way that these products are used. 

 Based on your research. Is there any advice that you would have for a pregnant person? 

Yeah, that's a good question. Learning as much as you can, , talking to your clinician, I think it's really hard to avoid these chemicals.

I don't want to put too much burden on pregnant women because they have a lot going on. I think my advice would be to talk to your doctor to try to understand what risk factors you should be most concerned about. And then, enroll in a research study, and then, I think with things like some acute [00:27:00] exposures, like we have wildfires here in Washington State.

There's been these really big wildfires in L. A. And I think, in those situations, I think we need to, be extra careful for people who are pregnant, who are living in these environments, because we just don't know what is happening. 

Yeah, that's good advice so more information is empowering and learn as much as you can , understand what to do in the future, and one thing that a lot of doctors say is that all pregnancy is a stress test, so, for example, for mothers who have gestational hypertension, they know after the pregnancy that they're at greater risk for having hypertension in the future, and they can be mindful of that information as they make lifestyle choices about diet and exercise. And as we learn more about these environmental chemicals and the placenta's translation of these chemicals into issues with the fetus, we can try to avoid the ones that have a bigger health impact, at least in the early trimesters of pregnancy.

Yeah, exactly. I wish there was a way that you [00:28:00] could measure environmental chemicals and there are some companies , you can measure some of them, but you can't go to your doctor and be like, Oh, I want a panel of my exposure to these chemicals. Right? And I think that's a missing gap. I think, when you enroll in a research study, there's been a lot of efforts by some of these consortiums to return results back to participants.

And it turns out people really want that data. 

That would be amazing, right? That's a great selling point to say, here's my placenta, let me know what you think. Because 

how can you even make a decision, how can you know, , how you should modify your behaviors if you can't even tell?

What, is happening and how much you've been exposed to. 

But right now, if you get a placental pathology, that's not part of it. 

No, it's really challenging to measure these chemicals. This is an ongoing problem. And that's why there's also now companies that do this. We measure these chemicals in maternal urine that we collect during pregnancy, but that only measures a very small time point of 24 hours.

So we're assuming that this one time point is reflective of all of pregnancy. And I think it [00:29:00] reflects chronic exposure. If you microwave your food in the same container every day, then your levels are probably inconsistent. But if you got a manicure the day before your levels are probably going to be much higher than normal.

So I think there are challenges with these measurements and it's because it's metabolized and excreted. It's not like you can measure them, but some people are measuring microplastics now and those you can go back in and see, but the problem is. That when we process these placental samples, we use plastic.

So there can be contamination from the plastic tubes. So that it's just really challenging. 

 This sounds really tricky, but like really important work. So thank you so much for the work that you're doing and for sharing it with us. 

Yeah, absolutely. Thank you so much for having me. This was great. 

Thanks again to Dr. Paquette for sharing some of her amazing work. You might ask, this tells us about risks, but what exactly can we do with that? Dr. Paquette mentions Michael Skinner, who articulates well what we can do, [00:30:00] and I'm paraphrasing here, but he suggests that we use the findings of studies like Dr.

Paquette's to aid in preventative medicine. Essentially what Dr. Paquette and others in her field are doing is creating a map for early stage diagnostics. We can use this information to invest more in preventative medicine to prevent the disease before it occurs. You can find Michael Skinner talking about this on a YouTube video on intergenerational transmission of environmental exposures.

I'll link to that in the show notes. If you liked this episode, please share it with friends. Thanks for listening. We'll be back next week with more amazing research.