Epigenetics, Hormones, Endocrine Disruptors, Microplastics, Xenoestrogens, Obesogens & Obesity, Inheritance of Acquired Characteristics | Bruce Blumberg | #145

About the Guest: Bruce Blumberg, PhD is a Professor of Cell & Developmental Biology at UC-Irvine. HIs lab studies epigenetics, gene x environment interactions, hormones & endocrine disruptors, obesogens & environmental toxins, and more.

Episode Summary: Nick and Dr. Blumberg discuss: Embryonic development; hormones and hormone receptors; estrogen & xenoestrogens; environmental toxins, obesogens, pesticides & contaminants; environmental causes of obesity; microplastics; how to avoid toxins in food & drinking water; and more.

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* Episode transcript below.

Full AI-generated transcript below. Beware of typos & mistranslations!

Bruce Blumberg 4:45

I'm a professor of developmental cell biology primarily at the University of California Irvine. And I started out as a developmental biologist and just trying to understand how does pattern form in in the embryo how does the embryo and able to self assemble to make a correct version of you or me or of your cat or your dog or whatever you have at the program is inside the embryo to develop that structure. And during the process of studying that I became interested in the role of small molecules that could activate hormone receptors on development. A great example of important molecules like that is retinoic acid, which is very important patterning molecule in early development. And from there, I began to look at molecules that looked like receptors, but we didn't know what the hormones were the bounds of those. So we call those in those days orphan receptors. And eventually, in studying those, and continuing our work in developmental biology, I realized that the intersection of identifying hormones for orphan receptors and developmental biology was the field of endocrine disruption. So that is, how do chemicals that we encounter in our diet and our environment affect the function of endocrine system? It turns out, there's quite a lot that do that. And we unexpectedly found a chemical that could make animals fat about 10 years ago, 1011 years ago now. And we decided to call such molecules obesogens. So we've been working on obesogenic endocrine disruptors, for the most part ever since then, for almost the past 20 years, now,

Nick Jikomes 6:28

I want to spend a little bit of time upfront talking about some, some basic biology, get some concepts in people's heads. So I want to talk about hormones. So what exactly are hormones? And how are they different from just other types of signaling molecules that that make our biology tick.

Bruce Blumberg 6:48

So classically, hormones are defined as molecules that enter the blood in one place, and act at some distant place. That's the classic endocrine hormone, for instance, cortisol or a straight die, or testosterone, or thyroid hormone. Those are the classic endocrine hormones. And these hormones Act are receptors that live in the nucleus of the cells. Okay, where they act as switches to turn genes on to turn genes off. And that's distinguished from other kinds of receptors, for example, a classic example would be insulin, so insulin access to a receptor on the cell surface, that triggers a cascade of secondary signals inside the cell that eventually has an effect in the nucleus to turn genes on and turn genes off. So the nuclear hormone receptors that we work on, have many less intermediates between the circulating hormone and the effect on gene expression.

Nick Jikomes 7:45

And so because because they're binding to these receptors in the nucleus, as opposed to ones that are on the cell membrane, Does that just mean that they can have a more sort of direct and fast action on changing gene expression?

Bruce Blumberg 8:02

More direct effect? Yes. I don't know if anyone's ever, ever contrasted how fast the action is, I would say they're both probably so fast that the difference isn't meaningful. And that they're less intermediates. Okay,

Nick Jikomes 8:17

so they actually get inside of cells get inside the nucleus act on receptors there. And so there's there's less in between them, and changes in gene expression, than there would be if we were talking about a molecule like insulin that's binding to a receptor on the outer cell membrane,

Bruce Blumberg 8:34

which has two or three or four intermediates. Now there's, there's nothing wrong with having intermediates, right. They provide a way to amplify or modulate the signal, and for the pathways to interact with others. Just saying it's different,

Nick Jikomes 8:48

I say, and is this the the bit about nuclear receptors? Is that baked into the definition of hormones? Or are their hormones that also interact with receptors on the membrane? Yeah,

Bruce Blumberg 8:59

so we're getting a little complicated now. So there are the nuclear hormone receptors. These are receptors for hormones that act inside the nucleus. But to be to be 100%, clear, some of those receptors can also find their way to the cell surface and have an action there. And some of them live in the cytoplasm and are moved to the nucleus when the hormone binds. So there's, there's there's different levels of refinement, if you will, and how they work. But the general concept is these nuclear hormone receptors. Receptors are a family of hormone modulated switches that turn genes on and turn genes off more or less directly.

Nick Jikomes 9:41

I see so so hormones, they travel at a distance, they can act away from where they're made, or they're secreted, and they activate receptors inside of cells to switch genes on and off ultimately,

Bruce Blumberg 9:54

that's a fair assessment. Yes.

Nick Jikomes 9:58

What are some of the ways that you environmental factors can influence gene expression via hormones and hormone receptors can can you talk about that a little bit, maybe just give Sure, thank you trying

Bruce Blumberg 10:07

to the exact same receptors. So the one of the chemicals we work on tributyltin binds directly to a receptor pair that controls the development of fat cells and the function of fat cells. So it acts just like the natural hormone, perhaps, not perfectly, so not with this high affinity are not as efficaciously. But they can bind to and activate or inactivate. So they interfere with the proper time in place of cellular signaling. And most of the work in the field has focused on the nuclear hormone receptors, and on those really just a subset. So if you talk to someone from the EPA, they'll talk about estrogen, androgen thyroid seems to be the only ones that they care about. But there are 48 Such receptors in humans. So there's a much bigger family to be studied. So we work on a different subset of that, that work on fat cells.

Nick Jikomes 11:07

And so when hormones are released under natural conditions, are they typically acting on multiple tissues simultaneously, like I often hear hormones as being molecules that orchestrate coordinated changes across different parts of the body, is that true? So

Bruce Blumberg 11:26

they act on any tissue that has the receptor. So if there's no receptor for the hormone, then there will be no reaction. It's really as simple as that. So any tissue in the body that expresses the receptor for hormone will be sensitive to the action of that hormone under most circumstances, and are

Nick Jikomes 11:45

they typically released into the bloodstream such that they're gonna go throughout the body and therefore interact with all kinds of tissues that that may or may not have those receptors. That's

Bruce Blumberg 11:53

the classic definition of an endocrine hormone. Right, for example, it's submit that's synthesized in the pituitary, and acts distantly, but hormones can also act on nearby cells, that would be sort of endocrine that would be paracrine. Or they could act on the same cells that that, that make the hormone that would be autocrine signaling. So all of those are possible.

Nick Jikomes 12:18

ICC so they can they can act at long distances, short distances, but they're secreted. They activate certain receptors, these intracellular cellular receptors, ultimately, the effect of gene transcription, then you said that endocrine disruptors are would be just any chemical that interferes with that normal hormone hormone receptor interaction.

Bruce Blumberg 12:37

That's correct. And it can interfere, it can make them more active, it can inactivate them, it can activate a receptor that would normally be quiescent because the hormone is not present. But now we have an endocrine disruptor. And the hormone receptor is active when it shouldn't be. And depending when that happens during development, you can have transient effects or permanent effects. Hmm.

Nick Jikomes 12:59

I see. I would imagine the earlier there's an endocrine disruption in development, the more likely it is to lead to an irreversible change. That's correct. And how do we so what are we talking about endocrine disruptors? You know, I would also imagine, right, as animals developing as the animals behaving in the world, it can do certain things or not do certain things that are going to modulate its endocrine system, and you can do things that might, you know, increase the amount of a given hormone that gets secreted or something like that. How exactly do we distinguish between normal sort of natural modulations of hormone activity in the body versus endocrine disruption?

Bruce Blumberg 13:38

So that's an excellent question. So that that raises the concept of an adverse effect, what's an adverse effect? Right, so how do we determine whether the endocrine disruptor has done something bad, or has just caused the transient effect that's of no consequence? That's a huge point of contention between toxicologists, people who study poisons, basically, and endocrine scientists who study the function of the endocrine system. So to an endocrinologist, anything that disrupts the natural function of hormones and their receptors is de facto adverse into a toxicologist will show me show me that you made the liver way more or show me that you that you caused this other effect. And we'll debate whether it's adverse or not. So it's a it's a it's a worldview type of problem. But wait, for example, we take powerful endocrine disruptors all the time. The birth control pill is a great example. And it disrupts the natural function of the reproductive cycle such that you don't get pregnant. And when you stop taking the hormones, within some period of time the function will normalize. But if a woman is already pregnant, and continues to take the pill As you may cause a very serious adverse consequence on the fetus that's exposed.

Nick Jikomes 15:05

What would that be? I've never heard of that. For example,

Bruce Blumberg 15:07

you could make a male fetus with diminished male and enhanced female characteristics. It doesn't happen in humans, but in many kinds of animals, you can totally sex reverse them. Or you could treat frogs or fishes with an estrogen, some kind of an estrogen and convert them all whether they're genetically Merrifield, male or female into females. So those kinds of effects can happen. So in humans, in mammals, it's much more that you cause effects on secondary sexual characteristics. Rather than complete functional changes, like male and female or female into male, that tends not to happen in mammals, including humans, but then in fishes, and frogs and birds, that can happen.

Nick Jikomes 15:59

And I would imagine that just because they have different sex determination mechanisms, it

Bruce Blumberg 16:05

works somewhat differently. Mechanisms not totally different, but the nuances are a bit different.

Nick Jikomes 16:12

And, you know, you hear a lot these days, I'm hearing more and more at least seeing more and more about Endo, endocrine disruptors in the environment. All sorts of things. People talk about Xeno estrogens, they talk about microplastics. They talk about pesticides. We're gonna get into a lot of this. But is it true that how much of this is that our environment is becoming more and more filled with endocrine disruptors versus we just didn't notice as much before?

Bruce Blumberg 16:42

Well, it depends on on who you're talking about. Right? So people in my field notice for a long time, the government regulators tend to notice less so they say what's there, but the level is too low to worry about. So there's this concept of a threshold. Right? So toxicologist, these poisons have a threshold of action. As long as you're below the threshold, you're safe. The problem is they don't ever test those thresholds. Those are inferred not they're made up numbers. They're not numbers based on biology.

Nick Jikomes 17:14

How do they infer those numbers? Well,

Bruce Blumberg 17:17

so the classic raise, you start, you treat animals with a certain amount of chemical and at high dose, it kills most or all of them, then you look for a dose that only kills half of them. That's the lethal dose 50, then you go down a little bit more, a little bit more until you till you see what's the lowest dose at which I see some effect. And by effect, I mean things like, did I disrupt the reproduction? Or did I change the weight of the brain? Or the liver? Or the pancreas? Did they do really gross things? My friend Tom Zeller compares it to taking your car to a mechanic and asked him to diagnose what's wrong with it. And he takes the car apart and weighs all the parts and says, Well, Nick, nothing's wrong with your car, because the parts all weigh the same. But then you get to some low level where there's no obvious effects. So they call that the lowest observed adverse effect level. And then they started applying mathematical formulas after that and say, Well, okay, this was done in a rat, and it's an adult study. So we'll put a 10 time safety factor. And if it's children, maybe we'll put another 10 Time safety factor. So we'll say at 100 fold below that we'll call that the Noel, the no observed adverse effect level, but then never tested, and just decided that there's there must be some threshold. I see.

Nick Jikomes 18:27

So even if you assume the math is appropriate, and the right scaling factors and things are used. Ultimately, it's based on those sort of gross anatomical defects that they observed judicially. And so if they're safe, there was a circuit rearrangement in the brain, or there was a more subtle change in hormone release, those things simply would not be captured. Absolutely. So that would, I mean, the natural extrapolation of this is probably a lot of those thresholds are set at places where we're we are getting some kind of effect in our bodies when we're exposed to these environmental contaminants. We just don't realize it yet.

Bruce Blumberg 19:07

Yeah, there's there's two other important concepts that aren't often discussed, or not discussed publicly as much as they should. The first is the concept of monotonicity. So it's actually encoded in law and the rights of all responses must be monotonic. That means that the sine of the curve never changes, right? So you can say more or less linear. And the only scientists to my knowledge, you believe that nature is linear, or toxicologists will not find any other scientist that believes nature always responds linearly to some kind of stimulus.

Nick Jikomes 19:39

Yeah. So a classic example of this would be, I mean, most drugs have a nonlinear response or an inverted U response where the dose goes up, you get more of an effect, but at some point, you increase more and it actually starts going down. You get a different effect.

Bruce Blumberg 19:52

That's absolutely normal. Right because the living systems have adapted If I have mechanisms to deal with excessive stimuli, so at some point when the stimulus becomes very high, that's the organism responds by turning off the, the production of new receptors, for example. So to dampen the response, imagine, you know, the fight or flight response, you get really, someone attacks you, and you get really, you know, the adrenaline starts pumping, and you get excited. Imagine if that didn't damp down after a while, what would happen to you, you would self destruct. So the natural hormone based systems and many other kinds of systems have regulatory components that prevents them from having runaway stimulation, so dampens the response. So the inverted U is a big problem. It's a big point of contention between the endocrine community and the toxicological community. And what was the other point I want to make? I forgot my other point,

Nick Jikomes 20:57

you said there was a couple of concepts or two, there was monitoring

Bruce Blumberg 21:01

monotonicity? I'll keep going. It'll come.

Nick Jikomes 21:07

Yeah, we can come back to it. Okay, so we've got all these thresholds we set because, you know, we have to, we have to set thresholds somewhere, by law, if we're going to, you know, do anything about you know, things in the environment. For all the reasons that you explained, there are assumptions baked into how we set those thresholds such that the thresholds are probably above where we're actually gonna see effects in the human body. And therefore, we're probably exposed to a lot of things, environmental contaminants that are below those thresholds set by toxicologists, but still having real biological effects on us. That's exactly right. Can you give us maybe a clear example of something like that, where we probably are, in fact, below the threshold of exposure that's been set, but where we know in humans that there's some effect that's, that's significant?

Bruce Blumberg 22:00

So let me make another point there. So that's a harm you said, where we know in humans, the problem, the problem is that we can't and we shouldn't do these kinds of experiments on humans. Right. So in animals, we can we can do cause and effect experiments, we can treat a population of some kind of animal with with or even cells with a chemical at some dose and observe the direct effect. You can't do that with humans. And you shouldn't do that with humans. So all you can do is say, in animal experiments, I see an effect that some exposure, some level of exposure, and humans are exposed to that level, therefore, I infer that there's a risk that should be investigated.

Nick Jikomes 22:47

I see. And so you know, even if we don't know, you know, we can't do this experiment in humans for ethical reasons. But Are there cases where, you know, based on the animal or if it's been done, and based on the levels that we know, certain things are found out in our environment, where they're, you know, very, very likely be effects that that are happening inside of humans? Sure.

Bruce Blumberg 23:10

There currently is a huge battle among the regulators and scientific community on chemicals like Bisphenol A, right. So in the US, the dose of Bisphenol A, that we're exposed to is allowed to be very, very high. Because it's based on studies done by industry that say, Don't worry, there's nothing going on. But then the European Commission was going to lower that level of exposure 500,000 fold based on a much broader review of the literature. And just to be clear, EPA FDA,

Nick Jikomes 23:45

no, no, no. BP the molecule BPA?

Bruce Blumberg 23:47

Yes. Okay. That's molecule BT BPA, right. It has other relatives that are equally if not worse. problematic. So in Europe, there's a big fight now. So the European Commission wanted to lower the dose 500,000 fold, and industry scream bloody murder, so that that fight is still going on. It hasn't taken effect yet.

Nick Jikomes 24:05

What industry?

Bruce Blumberg 24:07

Are we talking about here? The chemical industry, the plastics, people that make and use those chemicals?

Nick Jikomes 24:12

Got it. So this is a component of plastics? Yes.

Bruce Blumberg 24:16

And it's found and it's intended to be used in hard clear plastics. But this one always found them lots of other kinds of plastics to give them desirable properties. So for example, plastics are never just, you take this monomer and you polymerize it and now you have a bottle. For example, there's hundreds, if not 1000s, of other components in there. And there's a guy named Martin Wagner, who has studied he's taken various kinds of plastics just extracted them with water and alcohol and asked the question, what kind of activities do we find here? And then we find an activity what was the chemical and he found lots of chemicals and no one knew where they even there or have activities?

Nick Jikomes 25:03

And how do these things normally get into our environment? Is it like a physical shearing, like little bits of plastic just get physically broken off? Do they leach into solution, all of the above all of

Bruce Blumberg 25:13

the above. So the chemicals that the plastics themselves are in the environment, and you must be aware of the tremendous amount of plastic that just finds its way into the oceans, there's the Great Pacific Garbage Patch, and that there are those in every ocean, because the middle of every big ocean is a gyre where the circulation goes around that. And if you take anything, and you take, take a bowl, and put some stuff in there and swirl it, and everything goes to the middle. And that's what's happening in the oceans. So all the plastic that's getting dumped and finds its way, everywhere except being buried somewhere or burned ends up in the middle of the ocean, on islands.

Nick Jikomes 25:57

So that's not a good thing. And so when we hear about like, microplastics, in the news and stuff, I've been hearing more about microplastics in the environment, that's referring to, I would assume things like BPA and a whole host of other plastic compounds. Yeah,

Bruce Blumberg 26:13

some of those are intended to be small, right? You're doing face scrubs, and things like that they're there and tiny pieces, and others are breakdown products. Right, for example, the vinyl floor in your house, as you walk back and forth, it gets it gets degraded into dust. And that dust contains a lot of chemicals. Most of them not good for you.

Nick Jikomes 26:40

So like literally, if you're walking on a vinyl floor, year after year, you've been living in a home for decades, you're breathing in bits of vinyl dust basically. Exactly.

Bruce Blumberg 26:52

And there are people that actually gone to people's houses and vacuumed up that dust and asked the question, what kinds of activities do we find in here? And they find lots of activities, there's estrogenic activities. There's things that disrupt the thyroid, and there there are chemicals that affect obesity in there. Of course, the question is, are we does that does find its way into our bodies and cause and effect? And, you know, that's that's a that's a point that needs to be discussed? I believe that it probably does, but who can do the cause and effect experiments to prove it?

Nick Jikomes 27:32

I see. So it's a type of thing where someone like you, a developmental biologist and endocrinology person, you know, based on your understanding of biology, almost certainly, I think you would say that there's effects there. It's just we can't actually prove it, because we can't really do the experiments at the end of the day.

Bruce Blumberg 27:47

Now let's ask about the standard of proof. Right? This is another great thing. So in the civil law in the US, you prove something by a preponderance of the evidence, right, that it's more likely than not classic, you know, slightly more than 50% in one direction. And in the criminal law, we have the principle that it's better to let 100 guilty man guilty people go free than one innocent person to be convicted. So the standard is beyond the reasonable doubt. Interestingly, in the chemical law, the standard of proof is to a substantial certainty that a chemical will cause an effect in humans.

Nick Jikomes 28:24

So it sounds like you're telling me that it's stricter than it's an impossible

Bruce Blumberg 28:28

standard to meet. Right? Every time I talk to a lawyer, as I said, your standard of proof was so substantial certainty how many cases you're going to win? Not very many. So the chemical law is also rigged in that way. If you just had to prove by a preponderance of the evidence, then it's a much different game. Now, luckily, in court, if you say there's a chemical release, and there's effects, you only need to prove by a preponderance of the evidence that that effect was caused by the exposure. But in the regulatory arena, you need to show it to us if the EPA is to show those substantial certainty that the chemical is likely to be harmful to humans, before they can ban something. And that's really hard. I

Nick Jikomes 29:16

would speculate that the reason why things are set up this way is probably because there was a lot of industry lobbying to write the regulations this way. Of course,

Bruce Blumberg 29:27

I don't, I can't imagine any other way that it happened.

Nick Jikomes 29:32

When it comes to things like microplastics, and environmental contaminants, generally when we talk about endocrine disruption, I feel like I hear a lot about estrogenic effects and Xeno estrogens. I don't hear as much about androgenic effects. Is that are there more estrogenic effects that we know about that are actually out there? And if so, is there like a biological reason for that?

Bruce Blumberg 29:56

That's a good question. I think that the reason you hear more about that It's much easier for a chemical to be an estrogen than it is for it to be an androgen. I'm a little bit on thin ice here because I'm not a chemist. But basically, to make an environmental estrogen, you basically just need a ring and a hydroxyl group. And that's something that chemically and have some amount of estrogenic activity. So the estrogen receptor, I think is more susceptible to disruption than the androgen receptor. But I think it's also partly an historical issue. Right that the first disruptors that were discovered were estrogens. And the first meetings in the field that started to study the effects of these chemicals in the environment, where estrogens and the environment. Those were the meetings in the in the late 70s.

Nick Jikomes 30:46

And early they develop tools and did experiments that were geared towards those. Yeah,

Bruce Blumberg 30:50

I think that's, that's more historical.

Nick Jikomes 30:53

Interesting. So one of the other things that we're going to talk about are obesogens. So endocrine disruptors that then affect things like obesity levels, and epigenesis other aspects of metabolism. Before we get there, I want to talk a little bit about epigenetic as opposed to genetic inheritance. Sure. So can you provide just like a simple or basic definition here? What is epigenetic inheritance? Exactly?

Bruce Blumberg 31:21

Well, so the word Epi means on top of, right? So genetic inheritance is when you change the sequence of the DNA strand from you know, from the normal sequence of that when encode a protein, for example, and you change it such that the different amino acid is put in there. That's the most simple definition. Epigenetics effects whether genes are expressed or not. Okay, so if you imagine a tumor suppressor gene, and you mutate it such that it's, the protein is non functional, and someone gets gets a cancer as early as predisposed to get a cancer as a result. But if you have an epigenetic modification that prevents that gene from being expressed, same exact effect, no protein, but an entirely different mechanism of how you got there. And the kinds of screens that that have been done for many years, so called genome wide association studies looking for small changes in DNA and associating them with the presence or absence of a disease or other trait, miss the epigenetics. Now, we're starting to do studies that will be that will capture that, but those are still somewhat primitive. We're looking mostly just the DNA methylation, which is one subset of epi genetics.

Nick Jikomes 32:45

I see that oh, that's perfect. I was gonna be my next question. So what is DNA methylation and how does this tie in?

Bruce Blumberg 32:51

Right, so the the four bases that AC T and G, right, at the inside is in thymidine, guanine, some of them can be modified, especially cytosines can be modified on the methyl position on the five position, so you get five methyl cytosine, adenine can actually be methylated on the sixth position, and get six methyl adenine. And whether those are present or absent, has some effect on the biology of the DNA strand that we're talking about. It can affect its sensitivity to being broken down by cellular enzymes that can affect whether a gene is expressed or not expressed, depending on where it is, and how many there are.

Nick Jikomes 33:39

So these chemical modifications, these these methyl groups that can be added, or taken away, they can affect gene expression, without affecting the underlying DNA nucleotide sequence. Exactly. And so I know that there's, there's more to epigenetic modifications than that. But this, this ties into, you know, this ties into questions around like evolution and the interaction between the genes, the sequence of nucleotides that we inherit, and the environment. So like, classically, if you go back and look at the history of evolutionary biology, you know, we had Darwin's theory of natural selection, and that sort of merged with what eventually became an understanding of DNA sequences. And there was this sort of moving into the dustbin of this idea of the inheritance of acquired characteristics. So there were ideas that that you know, go back hundreds of years around, you can acquire a characteristic from your environment, something can happen to an animal as it's behaving around the world. And somehow the stuff from the outside in essence, it gets into the inside and can be transmitted to the next generation. Are there any, are there any clear examples that we know about today, where you have the sort of transmission cross generally of for phenotypes that were acquired from the environment. So let's

Bruce Blumberg 35:05

it's a difficult question, right. And I think we've had this battle in evolutionary biology for years, there was Darwin versus Lamarck. And then when Lysenko got involved, it kind of really trashed up the Lamarckian view. So it was kind of just forget about this, but seems to me in history, it's that very smart people are rarely completely wrong. So that's possible. But usually there's there's some insight there that might be valuable. So I think the idea of landmarks giraffe, right, that the classic story that the giraffe is an antelope that just kept stretching to reach the highest leaves, and that was passed on. That's, that's kind of silly, that that's not going to happen. But if you do what we do, or what Mike Skinner has done an expose an animal to a chemical, and that chemical makes the animal get fat, and it makes the children get fat and the grandchildren, the great grandchildren, great, great grandchildren. That seems to me that's pretty much a Lamarckian form of inheritance if you don't mutate the DNA, which we didn't, to the best of our knowledge. So I think that there that there is a role for the inheritance of acquired characteristics, but it's it's more subtle than the draft stretching its neck.

Nick Jikomes 36:23

Yeah, and I definitely want to jump into some of the work that you've done there. You mentioned briefly earlier, what obesogenic obesogens are, can you define one more time for people what an obesogens is? And also talk a little bit about if there are both non food and food obesogens? Sure.

Bruce Blumberg 36:42

So our definition is that obesogen is a chemical, that when you expose a living organism to it, the human or an animal, that organism either gets fat, or is predisposed to become fat, and a potential obese ijen is a chemical that you can show in some relevant test might do the same thing. So for example, we have cell based assays where if we treat the cells with a chemical, the stem cell will become a fat cell. And that doesn't mean that if you, if you expose an animal to the same chemical, you'll get the same result. Right, so we call that a potential obesogens. But I don't know of a single example, where we have a chemical that makes a cell and culture turned into a fat cell that doesn't also make an animal fat. Probably that will turn out to be some, but I don't know of any. So obesogen makes animals fat predisposes them to become fat, and a potential obese ajan is it gives a positive result in an assay that shows something related to fat function, more fat cells, more functional fat cells, fat cells that don't work, right, for example, that store fat, but don't release it. Things like that.

Nick Jikomes 38:00

Are there like food obesogens. So as opposed to just, let's, let's imagine like a fatty acid Balika, we eat those, we can break them apart and get energy from them. Obviously, if you eat enough of them, you eat more of them, that's going to push you towards the direction of getting fatter. Are there foods that in addition to being sources of energy, are also obesogens, meaning they have some other signaling function that either disrupt disrupts that they act as endocrine disruptors or something like that?

Bruce Blumberg 38:30

Well, I won't speak Entrepreneur on his behalf. But if you talk with Rob Lustig, who's at UC San Francisco, he will tell you that most kinds of sugars are obesogens. Right that not only do they add calories, but that they they disrupt the signaling system, such that you store yet more fat. And a lot of that has to do with making too much insulin, although not 100%, but a lot of it has to do with a burin, insulin signaling from the consumption of too many added simple sugars. Which now our diets now full of those, because in the 19, seven late 1970s, I think it was 1978. We had the McGovern report that said dietary fats killing Americans, we need to get rid of dietary fat. So we started doing that. So our fat consumption has gone way down since 1978. But if you look at body weight, and obesity 1978 is an inflection point. So after that, obesity skyrocketed in the US. And it's because we replaced the fats and food with sugars. That's not the only reason but that's a big reason that we are sugar consumption went up drastically.

Nick Jikomes 39:47

What were some of the first obesogens that you started working with in your lab? Well,

Bruce Blumberg 39:51

the one that we that we discovered, if you will, and that we still work on is called tribunal 10. Two interesting way we started studying tribunal 10 So, when I began to study endocrine disrupters, and started being invited to meetings to speak about our work, there was a huge effort in Japan to study the effects of endocrine disruptors and, and to inform the public of the dangers of endocrine disruptors is permanently led by a guy named Tyson Gucci. And I started getting invited to meetings in Japan. And tie had persuaded the Japanese government to measure the the levels of 20 highly probable endocrine disruptors in every body of water in Japan, from puddles to oceans. So I have somewhere on my shelf, a big fat book in Japanese, with the levels of these 20 chemicals measured all across Japan. So Thai persuaded me to test the effects of these 20 chemicals on a receptor that we were studying, that regulates how your body breaks down chemicals, regulates the so called xenobiotic response. So when your body encounters chemicals in the environment, or when you take pharmaceutical drugs, your body knows to break those down. And that that that that response is collectively called the xenobiotic response that involves a bunch of different enzymes, and transporters that, in principle should detoxify those chemicals and get rid of them. Now with natural chemicals, it mostly detoxifies and gets rid of them. With synthetic chemicals, there's no guarantee that processing it by that system will make it less toxic. Sometimes it makes it more toxic. So the classic example that is a compound in cigarette smoke called benzene hiring. So benzene hiring itself isn't so bad. But it's acted on by an enzyme in the body that makes it into an epoxide, which damages DNA. So the system that nature evolved to break down the toxic chemical, in this case made the chemical toxic. So that can happen. So we discovered when I was at the Salk Institute many years ago, this chemical, which we call the steroid and xenobiotic receptor, other people call the pregnane X receptor that is activated by chemicals, whether they're drugs or foods, or environmental chemicals and turns on this breakdown system. And the interesting thing that we found back then was that the system works a little bit differently in humans and mice and rats and other animals. And that is that there were chemicals that could activate the rodent receptor that didn't do anything to the human receptor, or some that activated the road and receptor that turned off the human receptor, and vice versa. So Ty said, can you test these 20 chemicals on SSR from as many species as you can get your hands on? So we started working on that. That's what got us involved in this. And one of those chemicals was tributyltin. And I remember I was at a meeting in the south of Japan, a little town called Matsuyama. The meeting is all in Japanese and I don't speak Japanese. So I'm trying hard to stay awake because I'm jet lagged. A few of the talks were in English. And one of the talks where am I forgetting his name right now. having a senior moment. I can't think of the professor's name, but he is from the HEMA University. And he said that tributyltin could sex reverse genetically female Japanese flounder and so what if we take this population of fish and we'll be 100% females and you treated them with tributyltin when their larva 30%. And that would become males? So as a developmental biologist, I'm pretty interested in that. So I called back to the lab and I said guys, can you extend the testing of TBT from just SSR and test the other all the other receptors and we had because I was at the Salk Institute, we had all those receptors and are in our inventory, if you will, because I was studying those when I was there. And we found out that it activated two receptors that were interested in. One was called our XR, which is a partner for about seven other receptors stands for retinoid X receptor. So it's a kind of retinoic acid receptor, but it's functions as a partner with lots of other receptors. And the other one is receptor it has the terrible name peroxisome proliferator activated receptor gamma P, R gamma, right, and that's an artifact of history that net leads or fatty acid receptors. But because the first chemical that was shown to activate the receptor was a peroxisome proliferator, that's where it got its name. And the names never been able to be gotten rid of. That's the way it usually goes. Yeah. So it activated those receptors. So he said, Okay, that's interesting. But now what because that's not what we were working on. That was a side project for us was only funded by by the Japanese government. And we said, Okay, well, let's test what it does to cells in culture. Can it make these pre fat cells into fat cells? Yeah, it did. Okay, now what Did we do we continue with this? Or did we drop it? Right? Because that's not our field. We didn't work on obesity. And nobody wanted to hear that. I remember the very first time I wrote a grant about this, one of the reviewers wrote in the review, how dare you waste our time with such a ridiculous idea that chemicals can cause obesity. Everyone knows that diet causes obesity. So it was tough to get that work funded, it took us probably three years to get our first grant to study that. But during that time, we build up quite a large amount of data that showed that this was worth working on. So that's how we got involved in that. That since then, that's grown to be all the work of

Nick Jikomes 45:48

this molecule that you mentioned TBT. What exactly is it? What are we what do humans use it for?

Bruce Blumberg 45:57

It's a, it's used in many ways. It's used industrially in PVC, plastics and all kinds of vinyl. Now tributyltin is not there intentionally. The chemical that's used in those is mostly dye, butyl, tin, and dioctyl 10. So 10 molecules with two chains of for two chains of eight. But tributyltin is there as a contaminant. Right. But the level of which it's a contaminant is way above the levels at which you need to activate the receptors. This is, when we started working on a tribunal tin was the single example of a chemical that caused the function in biology at the levels at which you found it in the environment. So you find that a parts per billion and parts per billion to turn cells into fat cells, parts per billion, it made mice get fat. So that's why we became so interested in because I, this talk about chemical causing or creating a hazard have an effect, according to scientists at work, and then the regular thing Yeah, but that's, that's such a low dose you'll never be it's way below the dose, which you find it is way below the dose at which we think it's going to be dangerous. So we only test chemicals at the doses at which you can find them in the environment. Because if it takes 1000 times more to cause and effect, that's not of interest to me, someone else can work on that I only want to work on chemicals that can have effects that the doses to which you and I are exposed. Makes sense.

Nick Jikomes 47:37

So before we get into some of your really interesting experiments that I was just looking at, I want to take one step back. So obviously, you're setting up the story that has to do with what obesity has to do with exposure to things in our environment. If we just look at the obesity epidemic, from a bird's eye view, and we look at the spatial and temporal pattern of obesity spread over time, you know, where it has risen faster, the types of people that's affected, which is basically everyone, and we look at, you know, it's sort of rate of change over time. When you think about sort of, just in principle, the different types of models that people have had out there for what could be causing this in principle, you know, there's, there's one school of thought, that is more or less than a lot of it has to do with genetics per se, that a lot of obesity is inherited in the DNA sequence. There's other schools of thought that say, well, it's mostly just diet and exercise and how much you move your body and how many calories you put into your body. And then of course, you know, there's a third potential piece of this puzzle, which is things like obesogens things in the environment, which might be promoting obesity. If you just look at the general pattern of obesity spread over time, does it get you thinking a little bit more or a little bit less in one direction? Is there anything at high level that can be ruled out?

Bruce Blumberg 49:05

I think the first thing to be ruled out is genetics. Right? The obesity pandemic has happened too fast, over too many large populations, for there to be have been a change in the underlying genetics. So I think genetics is is out as a cause of the obesity pandemic. Are there mutations that can make people predisposed to become fat? Absolutely. Are they spreading through the population at warp speed? Not a chance. So the primary paradigm and there are many people who vociferous Lee and angrily defend this point of view is that it's all about energy balance, it's simple matter of thermodynamics, that it's the number of calories you take in minus the number of calories you burn. And if you make that balance, that you are not going to gain weight. And that model has I mean it At some level, it must be true, right? You can't get that from breathing the air you have to, you have to incorporate more of the calories you consume into your body. Right. But the question is, how does that happen? So, most living organisms have a homeostatic control of us have appetite and satiety. Most animals don't eat, don't overeat, you won't go on safari and see very many fat animals. You don't see fat apples until you look at you know, our pets. And you look at domestic animals that we feed. So something is disrupting the homeostatic control of appetite satiety and weight. There's another very important model called the carbohydrate insulin model. It says, the amount of carbs simple carbohydrates in our diet are causing excessive stimulation of insulin, which is causing excessive storage of fat. So the carbohydrate insulin model does a pretty good job of explaining a lot of obesity because carbohydrates have gone up like crazy in our diet. But they don't do a good job of explaining the homeostatic control of weight and appetite and satiety. There's the obese engine model. And there's another kind of minor model called the the redox model for energy that says that the burning if you will a few molecules that consumption, the metabolism of fuel molecules makes a certain amount of, of reactive signaling molecules that affect appetite and satiety and metabolism. And then there's a resurgence. And I think we don't have enough data for epidemiology studies to say, to what extent obesogens are responsible for the obesity pandemic. But what we can show pretty convincingly in animals is that if you expose an our case, mice to very low doses of tributyltin, but they will get fat, and so will their descendants. So that, to me is the most fascinating thing, how are these effects of an environmental exposure transmitted to future generations without changing the sequence of the DNA?

Nick Jikomes 52:22

So you expose mice to TBT? That promotes obesity? How much DVT? Are you giving them? How are you giving it to them? And exactly how obese do they get?

Bruce Blumberg 52:32

Exactly? We're putting it into drinking water. Right, because that's how that's the simplest way that people get exposed, I don't know pump it down their throat or injected subcutaneously, we want to try and make a more realistic exposure, we're giving them 15 animal or so more or less 50 parts per billion, which is around the dose at which you can find in humans, you can find that the average in some studies in human blood was 20 nanomolar. So we're only giving them 50 in the drinking water. So how much is that achieving in the blood?

Nick Jikomes 53:06

And how do we think humans are ingesting this is it in our drinking water?

Bruce Blumberg 53:12

No one's measuring it, I can tell you. It's not a chemical that most water agencies measure. It's in many kinds of plastics, it's in the vinyl plastics in your home. TBT is used on some food crops Jesus might decide on on nuts and stone fruits. So we don't know a lot about where the exposure could be coming from. We just know that it's out there. And when you're looking at people, you find it. It's hard to measure. So not so many labs do a good job of measuring it. So that contributes to the uncertainty of to what extent are we exposed. And I'm not trying to say that tributyltin is what's making us fat. What I'm trying to say is here's here's an example compound, which we know is in the environment, we have a some idea of the level that's in the environment, we have some idea of what levels cause effect in animals, and those effects are permanent. What it does to our mice is it makes them free dispose to gain weight, when we up the fat in the diet a little bit.

Nick Jikomes 54:16

Okay, so not just automatically getting fatter when they are exposed to TBT. But when you increase the fat content of their diet somewhat, now they do. Yeah,

Bruce Blumberg 54:26

they get a little bit fatter on a normal diet. So a normal diet than normal mouse child is 13% by calories, fat. And at that level, if you keep them long enough, the animals whos