Tox in the Family: Generational Exposure and DDT

Blood samples and health records for 15,000 pregnancies provides a wealth of scientific data. Add samples and records from the resultant children and grandchildren, and you have an invaluable cohort with which you can study the long-term results of events that occur during pregnancy. Barbara Cohn with the Public Health Institute is the Director of such a cohort and discusses it with co-hosts Anne Chappelle and David Faulkner, including what she and colleagues have discovered about the generational effects of exposure to DDT and other substances.

About the Guest
Barbara A. Cohn, PhD, is Director of the Child Health and Development Studies (CHDS) at the Public Health Institute. CHDS is home to a groundbreaking study, which originated in 1959, designed to shed light on the various factors impacting health during pregnancy and early childhood. Between 1959 and 1967, 15,000 pregnant women and their families were enrolled. Researchers continue to study these rich data and conduct important follow-up studies to further examine how events during pregnancy impact the subsequent health of fathers, mothers, and their children and grandchildren. Dr. Cohn consults with researchers around the world on the use of the CHDS data for health research.

In addition, Dr. Cohn directs research examining how pregnancy protects against breast cancer and influences other health problems in mothers and their children in order to identify natural protective mechanisms that can be used for prevention. She also investigates whether early life exposure to environmental chemicals during pregnancy affects obesity, immune function, reproductive health, cardiovascular disease, diabetes, neurodevelopment, cancer, and health disparities in mothers and their children across the life span.

Dr. Cohn holds a doctorate in epidemiology, a master’s degree in city and regional planning, a master’s degree in public health planning, and a bachelor’s degree in zoology, all from the University of California, Berkeley.

Transcript

[00:00:00] Adverse Reactions “Decompose” Theme Music

[00:00:05] David Faulkner: Hello and welcome to Adverse Reactions. 

[00:00:08] Anne Chappelle: This season our theme is intersections, where we see toxicology intersect with another science.

[00:00:15] David Faulkner: Well, a lot of other sciences.

No person is an island, and no discipline has all the answers. But when scientific fields collide, some really interesting things happen. I’m David Faulkner,

[00:00:27] Anne Chappelle: and I’m Anne Chapelle. 

[00:00:28] David Faulkner: Welcome to Adverse Reactions Season 3: Intersections.

[00:00:32] Adverse Reactions “Decompose” Theme Music

[00:00:39] David Faulkner: Thanks for joining us. We hope you enjoy today’s episode, “Tox in the Family: Generational Exposure and DDT.”

[00:00:45] Barbara Cohn: You can’t have an obesity epidemic in less than 30 years because of a genetic mutation. It has to be a collaboration between some kind of susceptibility and an environmental exposure, so we believe there’s an environmental component. So, the question is, “What happens when you remove the original obesogen? You ban it.” Does generation four still carry the risk? 

[00:01:08] Adverse Reactions “Decompose” Theme Music

[00:01:12] David Faulkner: Hello and welcome to the Adverse Reactions podcast. I am thrilled to say that today we are joined by Barbara Cohn, PhD, the Director of the Child Health and Development Studies Program at the Public Health Institute. Welcome to the show, Barbara. 

[00:01:27] Anne Chappelle: Welcome.

[00:01:28] Barbara Cohn: Thank you for having me. 

[00:01:30] Anne Chappelle: I have to ask my standard question, which is: you’ve met my mom at the grocery store. She asks you what you do. Can you explain what it is that your role is right now, and what do you do at CHDS? 

[00:01:43] Barbara Cohn: Well, we have followed 20,000 pregnancies that happened in the 1960s for the health of three generations: the mothers and fathers that were giving birth then; the offspring, who are now 60 years old; their children who are the original grandchildren who are in their 20s and 30s. And then, we’re hoping to also follow the fourth generation that’s about to be born. And because these individuals were giving of their time and of their blood, we have archived serum samples from their pregnancies. We can look and see what’s in them and see if we can predict the health status of all three of these generations from those samples. 

[00:02:23] Anne Chappelle: Wow. Could you tell me a little bit about this cohort? How did you pick ’em? How did you find ’em? 

[00:01:22] Barbara Cohn: First of all, although I’m giving something away, I was eight years old when the cohort was first enrolled in 1959. I’m the third Director of this study, so this study has legs. It’s one of the oldest and largest such pregnancy cohorts in the world. And they were originally all giving birth or being seen at Kaiser Northern California, and it was originally a cooperative study between Kaiser and UC Berkeley. And it was an amazing time because more than 98% of the moms who were pregnant at the time agreed to participate, and they gave a very broad consent to follow their children and their own pregnancies. 

It’s an amazing study because in addition to having a very wide-ranging interview about their health habits and behaviors, we have blood from multiple points in time in their own pregnancies and from the fathers and partners that fathered the pregnancies. And we have clinical data abstracted from medical records directly about the progress of their pregnancy, their labor, and delivery; the health status of all the children through the age of five, including follow up if the people left the cohort, where they went. We found them to see how the kids were doing, and that’s because all problems that are related to pregnancy aren’t obvious at birth. Sometimes you have to wait at least five years to see how the kids are doing. And then, we had special studies after that where we looked at ages five, at age nine to 11, and then in adolescence, in subsets, depending on how much money we had. And in my tenure, we have done adult follow-up studies, the most recent of which was in the early 2000s where we did, for the women, a paired home visit where we visited the offspring mothers who were the daughters of the original cohort at around age 50-ish and their daughters, some of whom were children but many of whom were already in their 20s. 

And so, this is an amazing cohort, and we look at multiple health outcomes. And just to give you a couple of vignettes, we’re looking at the predictors of breast cancer in the mother’s generation, then the daughter’s generation, and risk factors in the granddaughter’s generation. We have looked at semen quality in the son’s generation. Sometimes, it’s hard to get that into people’s head that it still matters who your parents and your ancestors were.

[00:04:57] David Faulkner: That’s absolutely fascinating. It seems like such an incredibly large undertaking already, but I’m wondering what broad trends have you seen? My readings of the news media, it seems like everything is on the rise.

[00:05:12] Barbara Cohn: The health status of populations is not static. Unfortunately, I think there are many diseases that are on the increase.

Obesity is the most obvious change in our population. Families see it in their own households. You see it in schools, in parks. We have become extremely interested in the environmental exposures that exacerbate the opportunity to gain these excess pounds.

Obviously, you need food to get heavier, but the question of whether or not people are solely and only in control of what happens to the size and weight and shape of their body is beginning to look unlikely. And what that means is there’s a likely environmental contribution, and we have actually been focusing on legacy environmental chemicals. And our most recent papers on the granddaughter’s generation, who are in the age of 20 when we interviewed them and measured them, and we found a relationship between their obesity and whether the grandmother had high levels of the pesticide DDT in her blood at the time the granddaughter was in utero as an egg.

[00:06:22] David Faulkner: That’s incredible.

[00:06:23] Barbara Cohn: I need to go back and talk about that a little bit. The mother’s body at the time she’s pregnant is going through profound physiological changes. Everything from how her heart works, how her kidneys work, how her breasts develop to get ready to feed a baby—whether she breastfeeds or not—muscles, bones, brain; all of those organs have to adapt. So, this is considered a window of susceptibility for the mother and that the events of pregnancy can have very long-term impact on her health. And so, then, there’s the embryo, and this one’s the easiest one to understand. Every single organ cell system in your body develops at the time you’re in utero. That is considered a highly vulnerable period cuz little mistakes can have big outcomes. 

An example is that we’ve done some work on testis cancer and shown correlation between maternal alcohol use in pregnancy and also the pesticide DDT in the chance for testicular cancer later, at age 20 or 30. People are pretty sure it has an embryological origin, just a couple cells that are hiding out that didn’t do what they should do during development, and are prone to growth in a way that’s unhealthy later in life. 

Then, there’s the final group of cells. The third generation is also exposed in pregnancy to whatever the mom is exposed to. How? Well, in a girl, every single egg that she’s ever gonna have is inside her own ovaries while she’s developing in her mother’s womb. And what that means is what her mother eats and drinks and what she’s exposed to in the environment can reach that egg. 

Now, we’ve got these three generations, but they’re not in the same stage of vulnerability: there’s mom with all those organ systems being shifted about; there’s the embryo with all those organ systems developing; and then, there’s the promise of the grandchild, those are the germ cells that will form the grandchild. If it’s a boy, even though the boy doesn’t have eggs, he does have germ cells and stem cells that are also vulnerable at this time that will be used to manufacture sperm that will make his children. Increasingly, we understand from animal studies that there are ways in which alterations in these germ cells, alterations in the way organ systems are formed and alterations in what happens to a mother in pregnancy, that can have very long-term effects on health outcomes. 

But you can see that in humans, it takes 60 years to observe three generations, 70 years to observe four. And there are very few studies that exist where we’re able to do this. For that reason, my career goal has been to show that these data remain relevant to the current health status of human populations. And that includes things like immune function, the ability to form antibodies when you get vaccinated, the ability to fight an infection, the things that are heavily on people’s minds right now. We also study the brain, mental health, depression, anxiety. We are scanning the brains of some of our now 60-year-old individuals to understand how the prenatal environment influences the development of the brain, the connections that are possible, and the symptoms and suffering that may result. 

[00:09:48] Anne Chappelle: You’re enrolling more people, right? That are legacy people as others kind of fall off of your cohort?

[00:09:54] Barbara Cohn: We need to make it clear to the fourth generation how important they are. I just told you that three generations are all directly exposed to what the grandmother was exposed to, but generation four was not. So, generation four is interesting and important for us and, in my opinion, may be vital for understanding how to treat or prevent and protect the health of the generation now being born because we need to know if you can transmit some of these risks without direct exposure. We know it happens in animals, and there are potential examples of this that are certainly worrisome because the kinds of rapid changes and things, like getting colon cancer early, can’t happen only because of mutations in our germline—the genes that you think about when you think of eye color or hair color or a tendency towards a risk factor for diabetes, for example. When things happen very quickly, it means there has to be an environmental component. You can’t have an obesity epidemic in less than 30 years because of a genetic mutation. It has to be a collaboration between some kind of susceptibility and an environmental exposure, so we believe there’s an environmental component. 

So, the question is, what happens when you remove the original obesogen? You ban it. Does generation four still carry the risk? There have been some animal studies that suggest that they may. Some of those errors in the processing of gene instructions are reversible. We know that. And so, you might be able to have a drug target. You might be able to tell somebody how to help themselves. The idea here is if there’s a deficit or a change in somebody’s genetic instructions that’s producing too much of a metabolic chemical in their own body, we might be able to fix that by driving that metabolic process in a better direction. 

[00:11:57] Anne Chappelle: Your first cohort, your F0s: they had a more controlled exposure scenario, let’s say, because of where they were, but future generations—maybe they’ve spread out across the country or we have different quality for different things—but that’s gotta be difficult to control that as it continues to spread. 

[00:12:22] Barbara Cohn: It’s challenging, and it’s only impossible if you haven’t carefully collected biospecimens and decided what you think is important to know about these people. You have to be somewhat clever about how to address this cascade of changing exposures. There is no stable exposure. It doesn’t exist. So, it changes every day in your own body. Just think about what you eat, cuz that’s an exposure. Just think about one day, the air is nice and the next day its awful. What you have to do is decide that you measure what you can measure and you acknowledge what you can’t. So, in a human population, you can’t put people in a cage and just observe them for 60 years. So, it’s not possible to do causal experiments in humans. These observational studies, though, are a key to the laboratory and in vitro work that have to be done follow them forward. 

But then you have the problem that what these people were exposed to in 1960 has altered as we make policy decisions, as the chemical manufacturers make new choices and have different markets for chemicals, and as regulatory bodies make changes. And then, each generation has a pile-on of additional exposure. In our own cohort, there are fluorinated compounds that were present in the 50s and 60s, and we also have BPA in our blood samples in the 60s because those cans were lined in the 1950s. For the fluorinated compounds, there was an agreement by the manufacturers to change the format of their manufacturing of fluorinated compounds because they are very persistent, and they decided they would try to change the way they made these chemicals. So, if you look at the blood of our F0 and the blood of the F1, they don’t have the same proportionate amounts of those fluorinated chemicals. 

[00:14:20] Anne Chappelle: Your background is epidemiology, but this season of Adverse Reactions is really about intersections with other disciplines. And this is a really perfect example of the intersection between toxicology and epidemiology. I almost think of, it’s like you’ve got this fantastic store, and somebody has to come to you cuz you’ve got all these different ingredients and you can pull all that together to make some really fancy and delicious conclusions. There’s got to be some other ways or other kind of intersections that are really important to keeping your cohort alive.

[00:15:04] Barbara Cohn: Absolutely. And the first thing I wanna say, if you get nothing else out of this podcast, there is a purpose, a reason, and a reward to collaboration. Because collaboration and transdisciplinary work costs time, costs money, and sometimes because of the way we are siloed and evaluated in academia and other places, including study sections, can cost you grants and tenure. This has to end. 

[00:15:34] David Faulkner: How should we think about these results or these findings with respect to the types of testing that might be worth doing for things? If we’re thinking about product safety, we’re thinking about drug safety, thinking about chemical safety, what might we incorporate based on these findings that you could have these effects in F3 that weren’t even exposed directly to the thing because of an F0 exposure. What are the ways that this is used to influence like policy or other kinds of decision-making? 

[00:16:06] Barbara Cohn: It’s a really good question. I have several examples, but I’ll give you two. The first is: every once in a while, the organization that declares something a carcinogen, IARC, meets, and DDT has always been on the fence. There was a big controversy about whether DDT causes cancer. If you’re aware of the Long Island Study of Breast Cancer and there were other smaller studies suggested that it did cause or was associated with cancer.

And then they’re the animal studies that have been somewhat few and far between. Because why? We banned it in 1972. Why to go get a grant? Why bother? The only reason of course to bother is it (a) it’s still in the environment, (b) it’s still being used worldwide in lots of places, and (c) the ancestral exposures are still with us. We all still have metabolite in our body, and we were, most of us, exposed in utero. I don’t know when you were born, but I was born in 1951, maxed out in ’59. I was exposed before puberty, and most of you were exposed as fetuses or germline. 

When IARC met the last time, we did a paper on the relationship of in utero exposure to the DDTs and breast cancer in the daughters, and the committee considered it and moved up the designation for DDT. Now, what does that do worldwide? It’s complicated because scientists provide information for policymakers, and some scientists put themselves in the position of making decisions. Sometimes they’re good decisions, and sometimes they’re not. Scientists are just people—they’re not perfect. But my personal goal was always to provide information that people could use to make things better. That was the whole purpose. And so, that’s one example. 

The other example is there’s more than just synthetic estrogens that are given to women in pregnancy, and starting in the 1950s, there were synthetic progestins also given to women in pregnancy. So, progesterone is a hormone that quiets the uterus, and it is heavily produced by the placenta in the second trimester of pregnancy and its sort of replacement is HCG in the very beginning of pregnancy. And so, when women had bleeding in pregnancy—threatened to miscarry—people thought that they might give that woman progesterone or a form of progesterone, in this case a synthetic progesterone, a progestin that might stop her from expelling the fetus or the embryo. These drugs started to be used really early on, including during the time our cohort was collecting data, and I told you before, we know every pharmaceutical these women received. Progestins are really complicated compounds, and they, in some form, they act like androgens. And sometimes they act like anti-estrogens, and they’re metabolized in odd ways. So, we did discover that the women who were given this progestin in pregnancy in our cohort, that their children had a higher risk for a number of different cancers. And we published this in a clinical journal. Why is that interesting cuz it’s 1960? 

That’s because one of the components of this current drug that is being given to women to prevent preterm birth, called Makena, has that as an ingredient. The drug itself has been through multiple names and companies over the years. The FDA had given an emergency authorization to Makena, and there were two subsequent clinical trials that showed unlikely effectiveness for preventing preterm birth and the FDA was working on a recommendation to remove the authorization. But in the meantime, our study came out, and they used it. They used it in the response to the response of the company. Here we are an ancient study. Our work was not the only information that they used. That evidence was helpful. So, that’s an example. 

[00:19:52] Anne Chappelle: I did wanna ask about your education a little bit. You’re an epidemiologist, but you also have degrees in city and regional planning, public health planning. I mean, it almost seems like you were destined for this role. 

[00:20:06] Barbara Cohn: I chose epidemiology because it was a way of providing information for change. Not everyone chooses epidemiology for that reason. The questions an epidemiologist asks, you can get yourself entangled in some really interesting mysteries that mean less than other mysteries, and some of the mysteries that challenge the status quo or existing health policy are ugly because people attack you—like when you write a paper about DDT and someone says in the Wall Street Journal opinion page that you don’t know what you’re talking about because it’s an assault on free markets. But I really think that it’s very important for epidemiologists to go beyond what they usually do, which sometimes is, they’re interesting intellectual arguments, but they may not be as meaningful as they could be. The questions you ask matter, and your background does partly determine the questions that you ask—plus your education and trainings—which means that programs in epidemiology need to emphasize the problem of trying to decide what to put your really well-honed, fantastic skills to. And you have to open yourself to doing new things. The new data tools for studying mixtures are completely beyond what many people were taught, at least in my time. You have to be open to learning new things and making change. I don’t know that that’s emphasized in some, maybe it is, but if it’s not, it should be.

[00:21:36] Anne Chappelle: We do ask every guest, what was their biggest adverse reaction?

[00:21:42] Barbara Cohn: Well, there were two, but the one that I think is most interesting to your readers is that because we were the only ones that had exposure timing data when we worked on DDT. The prior studies that used middle-aged samples in case-control designs where people were already sick or where the data were amalgamated together refused to believe my work for a number of years. The reviews that I got back were unreasonable and not scholarly, and they were clearly … they weren’t deliberate, you know, sabotage, but it was narrow-mindedness, closed-mindedness. It was extremely frustrating to me that a different idea had no place in science cuz I always thought that’s what science was about. It made me think, “I’m just gonna keep fighting. I’m not quitting. I need to do good work.” I like very much to hear from people when a good criticism or a good idea is really very important, but I was supremely disappointed in the system, not necessarily the people, when it seemed impossible to me that they could not see what kind of contribution this study could make. 

[00:22:52] Anne Chappelle: Well, I’m glad that you’ve shown them wrong.

[00:22:55] David Faulkner: Yes.

[00:22:56] Barbara Cohn: I think I have. I was like the little engine that could, “I think I can.” I’m still doing it. 

[00:23:00] Anne Chappelle: Well, thank you again so much.

[00:23:02] David Faulkner: We really appreciate having the chance to talk with you today. This is fascinating work and really important work. So, thank you so much.

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[00:23:16] David Faulkner: On the next episode of Adverse Reactions, “The Big Picture of Small Things: Nanotoxicology.”

[00:23:24] Tim Nurkiewicz: When the field of nanotoxicology was originally coined or came about, it was on the notion that nanomaterials would display a different toxicity than their larger counterparts. And over the years, what we’ve been observing is not a different or a novel toxicity, but rather we’ve shifted the dose-response curve.

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[00:23:51] Anne Chappelle: Thank you all for joining us for this episode of Adverse Reactions presented by the Society of Toxicology. 

[00:23:57] David Faulkner: And thank you to Dave Leve at Ma3stro Studios, 

[00:24:00] Anne Chappelle: that’s Ma3stro with a three, not an E 

[00:24:03] David Faulkner: who created and produced all the music for Adverse Reactions, including the theme song, “Decompose.” 

[00:24:09] Anne Chappelle: The viewpoints and information presented in Adverse Reactions represent those of the participating individuals. Although the Society of Toxicology holds the copyright to this production, it has, 

[00:24:21] David Faulkner: definitely,

[00:24:22] Anne Chappelle: not vetted or reviewed the information presented herein,

[00:24:26] David Faulkner: nor does presenting and distributing this podcast represent any proposal or endorsement of any position by the Society.

[00:24:32] Anne Chappelle: You can find out more information about the show at AdverseReactionsPodcast.com 

[00:24:38] David Faulkner: and more information about the Society of Toxicology on Facebook, Instagram, LinkedIn, and Twitter. 

[00:24:44] Anne Chappelle: I’m Anne Chappelle, 

[00:24:45] David Faulkner: and I’m David Faulkner. 

[00:24:47] Anne Chappelle: This podcast was approved by Anne’s mom.

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[00:25:00] End of Episode