About the guest: Angel Nadal, PhD is a biologist in Spain whose lab studies endocrine disruptors (e.g. microplastics), hormones (estrogen, insulin), and the endocrine functions of the pancreas in health & disease.
Episode summary: Nick and Dr. Nadal discuss: endocrine biology of the pancreas; insulin and estrogen signaling in the pancreas; BPA, microplastics, and other xenoestrogens; pregnancy & fetal development; effects of hormone disruptors in males vs. females; and more.
Related episodes:
M&M 145: Epigenetics, Hormones, Endocrine Disruptors, Microplastics, Xenoestrogens, Obesogens & Obesity, Inheritance of Acquired Characteristics | Bruce Blumberg
M&M #124: Hormonal Contraception, Sex Hormones, Menstruation, Pregnancy, Puberty, Estrogens, Androgens, Effects of Birth Control on Cognition | Adriene Beltz
*This content is never meant to serve as medical advice.
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Episode transcript below.
Full AI-generated transcript below. Beware of typos & mistranslations!
Angel Nadal 1:29
Well, I really began to study chemistry in my hometown, which is the country in the southeast of Spain, and later I moved to the Autonomous University of Madrid to study biochemistry and molecular biology. And after that, I decided to come back to adante, where is a very an excellent Institute of neuroscience. And I did my PhD in that Institute, although I work with beta cells that are not really neuron but from a electrophysiological point of view, we were interested in in studying this stimulus secretion coupling in pancreatic beta cells, and how the electrical activity of the beta cells drive to the calcium signaling that produces the release of insulin in those cells. So it makes sense to study that being in an institute of neuroscience, I mean in the sense that we were very interested in ion channels and and calcium signaling and those stuff. So I did my PhD there, and later I moved to King's College London, UK to do my my postdoc there. So I stayed in King's College 40 years, and I was studying the connection between calcium signaling and subdivision in astrocytes. I was really in a group of neuroscientists and working particularly on that how proteins such as albumin that were trying France going through the blood brain barrier. What the blood brain barrier breaks down, activates astrocytes and make them to divide and produce a scar, you know, this sort of stuff. And really it was in London when I first learned about genderclinic ruptures, that was at the mid 90s, and also about the extra nuclear actions of pesto Ian receptors. So at the end of the 90s, I moved to Alicante because they open a new university here, and they contact me so to go back, let's say, home, and starting this new university. And yeah, I decided to begin working in estrogens and endocrine disruptors in in the pancreas, in the endocrine pancreas, the beta cells. So that's more or less my background. Yeah,
Nick Jikomes 4:31
yeah. No, it's, it's an interesting background. And you know, even though we're going to talk probably mostly about the pancreas, and you know, endocrine aspects of the pancreas, hormone secretion, insulin, estrogens, things like this and endocrine disruptors. I think it's worth reminding people that we'll probably talk about the brain to some extent, at some point, maybe. But even though we think about like the pancreas as an endocrine organ, and we don't think of it like a neural organ, because. Is, you know, it's obviously very different from the brain. At the same time, much of the brain, important parts of the brain that we might talk about are neuroendocrine organs themselves. They also secrete hormones. And, you know, even though the pancreas isn't made out of neurons, like the brain is, you know, part of your your studies were setting the electrical properties, ion channels, all these things that we normally associate with neurons are found in other cells as well.
Angel Nadal 5:23
It's actually that, well, I think I consider myself a beta signaler, and so the beta cell works very much as a neuron. From that point of view, it's an excitable cell. It produces axion potential. And are these axial potentials, which code, finally, for the insulin release, very similar to what a neuron does for neurotransmitter release.
Nick Jikomes 5:51
Yeah. So, yeah, let's talk about the pancreas a little bit. Just to give people some sense, you're referring to the beta cells. So these are a major cell class, if I understand correctly, they're a major cell class of the pancreas, and these are the ones that secrete insulin. You're actually saying that analogous to the way that a neuron will release neurotransmitters in response to a change in electrical signaling within the cell, something similar is happening to regulate insulin release from these beta cells in the pancreas.
Angel Nadal 6:21
Yes, the pancreas. We have two types of pancreas, the exocrine pancreas, which is not related to to the endocrine system, and the endocrine pancreas, which are islet of Langerhans, are called, which is the basic physiological unit of the islet of the endocrine pancreas. And we have, in humans, million of them inside the pancreas. So each of these islet contains between 1500 to 3000 cells of five different types. The majority of dots five type of cells is the pancreatic beta cell. In human it's about 50 to 60% of the islets are pancreatic beta cell, and about 40% are glucagon released in alpha cells, and the reds are minority somatostatin releasing cells and others in mice is a little bit different. They contain more beta cells, so about 80% of the cells in the islet are beta cells, and they contain less alpha cells releasing glucagon about 10% 15% so that makes a bit of a change when we compare the situation in mice to the situation in humans, I see
Nick Jikomes 7:57
so one portion of the pancreas is devoted mostly to endocrine functions. So this is the one that people probably hear about most that's associated with insulin and blood glucose regulation. Basically, you're saying that chunk of the pancreas is composed of what we call islets. So these are basically patches of tissue, each of which contains a certain combination of cells, such as the insulin secreting cells and others, exactly, yes. And so, you know, I don't want to spend too much time on this, because I've covered it on the podcast before, and I think people are most familiar with this part of the pancreas, and we're going to also talk about other things pancreas does that I think people don't appreciate as much. But can you give us just a very basic, very simple rundown of how these beta cells and cells in the endocrine portion of the pancreas regulate blood glucose levels via insulin.
Angel Nadal 8:50
Yes, the pancreativa cell is the cell that produces insulin. It Express insulin and biosynthesize insulin, and is the only cell really that is able to release this insulin in response to nutrients in our body. And that's very important, because insulin is the only hormone able to decrease but blood glucose, the only one, the only one we know about. So if the pancreatic cell goes wrong, yeah, then we get diabetes, yep, and that's why, why it's very, very important for for all of us. So normally, after a meal, what we have is an increase in in blood glucose, and this is because the, well, the digestion, and there is, of course, increase in glucose, amino acid and fatty acids, and they go to the pancreas. Beta cell, so the pancreatic VHS cell, if we focus in glucose, uptakes, glucose, metabolize glucose, glycolysis and the Krebs cycle, and produces an increase in ATP ADP ratio. And this connects to the to the channel at the pragma membrane, which is the ATP sensitive potassium channel that controls the resting membrane potential of the cell. So when the ATP increases, this channel crosses potassium stops going out of the cell, and then the plasma membrane, the polarizes, opens calcium channels. What it gets calcium channels, and calcium gets in the cell and produces the exocytosis of insulin, and then insulin is released in into the blood. Yeah, and this is
Nick Jikomes 11:03
like what you were talking about before. It really is a lot like neuronal transmission in the brain. In many ways. There's ion channels that are coupled to ATP, ADP levels in the cell. So you know, metabolism is being coupled to channels that regulate the potential of the cell, and when the cell becomes sufficiently excited, certain ions come into this so there's like a more abundant ATP. This causes things like potassium and calcium to flow back and forth between the cell and at a sufficiently altered membrane, the cell will then release, in this case, insulin, not unlike the way that a cell in the brain might release neurotransmitters, yeah.
Angel Nadal 11:45
SRG, that's it interesting.
Nick Jikomes 11:47
That's it. Okay, so insulin gets released, and basically it's telling the body take some of that glucose out of the bloodstream and, you know, store it in cells.
Angel Nadal 11:56
Exactly. Insulin has receptors in in in different tissues, but mainly it works at the liver, skeletal muscle, the adipocytes, and also in the brain. So what it's insulin says to the skeletal muscle, this uptake glucose, and indeed, is the skeletal muscle, the tissue that takes more glucose away from our blood, tells the adipocytes also to uptake glucose. And the excess of glucose is stored. You know, it produces lipogenesis, and it tells the liver to stop producing glucose, which is the function of the liver in terms of glucose homeostasis. And it also tells the brain that insulin has been released and there is nutrients already there, you know,
Nick Jikomes 13:00
yeah, yeah. So it's serving more food intake, yeah, yeah. So the insulin is not only telling parts of the body, like, like the liver, to store the glucose and basically save it for later, but it's also telling the brain, like, basically, that we just ate. It's important for instigating some of the satiety regulating mechanisms of the brain, saying We just ate something. There's nutrients, prepare the organism to deal with that.
Angel Nadal 13:25
That's it.
Nick Jikomes 13:27
And so this is, this is a core, core mechanism of the body. It's super important that blood glucose levels don't get too high or too low. Insulin secreted from the pancreas. You're saying the pancreas is the only, these are the only known cells in the body that secrete insulin. So it's extremely important, in that sense, what is so important about preventing glucose levels from getting too high for too long? What are the things, some of the things that start to go wrong if glucose remains elevated? Yeah.
Angel Nadal 13:55
I mean, if glucose remains elevated, it starts to affect mainly endothelial cells and the vascular system, and that begins to produce problems. And this is common. I'm not an MD, but I know a little about that, and is common in diabetic people for many years, to have complications with the in the eye, for instance, the retina, and to have problems of vision, to have diabetic food because of this lack of micro vascular tissue which is affected there, it affects the heart and makes you more of a bigger probability of a heart attack and other other things. So really, having high levels of glucose for. A long period of time, is, is, is nasty, so is to our organism, yeah, yeah.
Nick Jikomes 15:09
And I can, I mean, on a sort of coarse grained, intuitive level, I would imagine, you know, glucose is fuel for the cell. It's like a primary fuel source for all of our cells. You don't want to give them too much too often, I guess, you know, maybe an analogy would be like, you know, I have my laptop here, and it's plugged into the power source, but the power source has a specific voltage that's sending a specific amount of power. If I was to hook this up to a massive generator that would send too much power all at once, you know, I couldn't blow out some of the circuits of my computer. Yeah, yeah,
Angel Nadal 15:39
that's it. I mean, the point is, we always need to regulate glucose very accurately. You know, the beta cell is prepared for that. So it's prepared to have a response in terms of insulin release to a very small amount of insulin. It can distinguish between six millimolar to 6.1 millimolar, you know, I see it's highly 2 million, very highly sensitive to door changes and and we need that to properly adjust the tissues that I just mentioned, like, like the adipocytes and the liver, etc, to to control and maintain the glucose levels as constant as possible.
Nick Jikomes 16:33
I mean, it's just a highly sensitive control system. Yeah. So I want to ask you, I know that I think this ties into a lot of the other stuff that we're going to get into. But basically, a big part of the pancreas, as we said, is is an endocrine organ. One of the major hormones that is being secreted is insulin. That's what we just talked about. But there's probably a bunch of other sensitivities here to other hormones and other signaling pathways tied to other hormone systems. Can you start to talk about some of the other hormones that the pancreas is sensitive to? For example, I know that you've done a lot of research on things like estrogens, so how do some of these other hormones fit in to the picture when it comes to the pancreas? Yeah,
Angel Nadal 17:13
I mean, there are different hormones that can control the insulin released before entering into ES perhaps it's easy to think about, when we are stressed and adrenaline is released, that what it does is to decrease insulin response to glucose so that we have more glucose in blood to go running, you know, yeah, yeah. If I need to run away, we need it, you know, yeah, yeah. If we are in in danger, we have to to run. So adrenaline, of course, affects the pancreatic cells in that sense. And later, there are other hormones that may have a more long lasting effect, such as estrogens, for instance, which is, are the female hormones? And we are interested in how particularly estrogens affect the pancreatitis health and because the islet of Langer has the endocrine pancreas adapts to pregnancy. It has to adapt to pregnancy. This a very interesting period pregnancy to study from the physiological point of view, very difficult as well. But during pregnancy, Walmart has an increase in tissue because of the features the placenta and all that this is growing and the pancreas, her pancreas, needs to adapt to that increase in tissue. So therefore, there's an increase in the number of pancreatic beta cell. There is also an increase in how cells senses glucose. They start sensing glucose to low levels and secreting more insulin. And in part, this is produced by Stradivari and other hormones as well that are particularly going up during pregnancy as placental lactogenes.
Nick Jikomes 19:27
Interesting, interesting. So, yeah, this makes perfect sense. So obviously, when a woman gets pregnant, there's a there's a growing fetus inside of her womb, she's going to need to provide nutrients and energy to the growing baby. And so it makes perfect sense that something like this system would have to change, because it has to. It has to adapt to that change in the woman. You're gonna have to provide extra nutrition for the two bodies now instead of the one. And if you know to anticipate maybe some of the places we're gonna go, we're. Yeah, it also makes perfect intuitive sense that something like an estrogen would regulate that process, because estrogens are naturally going to be fluctuating over the course of pregnancy, and so all this stuff is hooked together so that there's these metabolic adaptations in response to these hormonal changes triggered by pregnancy. But I would also imagine if estrogens instigate those changes in the pancreas during pregnancy, changes in estrogens in other contexts, would probably naturally alter pancreatic function as well. So if we're, for example, living in an environment that is highly estrogenic, because we're exposed to estrogens in the environment that could potentially affect insulin signaling and pancreatic function in everyone, not just pregnant women. Yeah,
Angel Nadal 20:39
indeed, that was the idea when we started with our project using Bisphenol A, which was known to be a sino estrogen, but was known to act as an estrogen. It's a weak estrogen that people said that that was 25 years ago, something like that. So the idea is, okay. If this is working like estrogen is, is doing the same as the natural hormone to pancreatic beta cells in mice. So that we start doing is giving Bisphenol A and stradio, the natural hormone, separately to male mice, they never had to be exposed to these doses of an estradiol compound, as Julius mentioned so and Then we discover something that was fascinating from the scientific point of view, but scary from the personal point of view too. And is that Bisphenol A at low doses was producing insulin resistance and hyperinsulinemia in mice and and it was affecting insulin release and other peripheral tissues as well in adult in other mice, that that was the first Yeah. So basically,
Nick Jikomes 22:11
when we think about things like insulin resistance and type two diabetes, which we'll probably talk about in different ways, normally, I think a lot of people, when they think about why someone becomes diabetic, they think about, you know, if it's type two diabetes, at least, that this is induced by the diet, that it has to do with sugar and carbohydrate intake. And indeed, those things are very important. But I think what you're starting to say is that you can get insulin resistance by other means. There you could be exposed to certain hormones, for example, or certain endocrine disruptors. And you know, even in the absence of, say, you know, drinking Coca Cola every day, you can still develop insulin resistance in those ways.
Angel Nadal 22:49
Yeah, exactly. I mean. What I think we know now is that many of these endocrine disruptors that we are savvy are part of the diet as well. For instance, Bisphenol A tallate and other bifid us are part of our plastics component, components. And I mean, they are in food contact material. So when we buy something that is involved in plastic. So this plastic is going to release these bisphenolS, phthalates and other chemicals. You know, plastic contain hundreds or 1000s of chemicals. It is not only a polymer, yeah, and I think this is part of our diet as well. So we always thinking, okay, lipids, sugars, and of course, as you said, this is very important, and it's no doubt that they affect, you know, insulin sensitivity this and glucose is an auto vetogenic In general, the excess, but there are other chemicals in food coming from other sources.
Nick Jikomes 24:09
Yeah, yeah. And for better or worse, for better or worse, these things are in our food supply, and to some extent, they're unavoidable. You know, a lot of the stuff is fascinating, but a lot of the stuff, you know, the stuff you work on, is fascinating, but it's also terrifying. So a lot of the stuff is is, is going to be pretty unsettling, maybe, to people who haven't, who haven't looked into how widespread these endocrine disruptors are. But before we like really dive into some of that stuff, I want to talk a little bit about estrogen signaling and estrogen receptors and sensitivity in the body. So obviously, the body has natural estrogens that it produces. As you mentioned, we've got BPA and other xenoestrogens, artificial estrogens that we're going to talk about. Can you say a little bit about estrogen receptors? How many estrogen receptors are there, and is there anything sort of special or notable about them in terms of their sensitivity? Or how they work. That's going to be important for understanding some of the other things we're going to talk about. Yeah, there are
Angel Nadal 25:08
three Australian receptors two of them that are the more classical ones are Australian receptor alpha and Australian receptor beta. They are. They belong to the so called family of nuclear receptors, and they classically act as transcription factors. So they bind the Liga, the natural hormone in this case, 17 beta stradio. They dimerize. They go to the nucleus, or are already in the nucleus, depend on the cell and bind to an estrogen response element in the DNA, and that puts all the machinery of transcription to work, okay, and increases gene expression. And there is another type of response which of this very same result does, which is not in the nucleus, is an what we call extra nuclear initiated effects. So in the last 30 years, they have been a many different studies that have been published to show that these receptors here, alpha and i beta are able to activate kinases outside the nucleus, such as bi free kinase Eric, one, two mat kinases in general, and then to regulate other proteins or signaling pathways, including ion channels. So we have like two ways the cell respond to estrogens, in terms of estrogen receptors, the nuclear one, which is the very classic one, and the extra nuclear, which is rapidly initiated and activates a signal Nick. And this one is very, particularly important in terms of endocrine disruptors
Nick Jikomes 27:17
I see. So oftentimes, when we when we think about a receptor, they're often located on the outside of the cell, and the cell responds to something on the outside, and this leads to changes on the inside of the cell. But for some of so for these estrogen receptors, they are internal receptors. They're either located in the cytosol or in the nucleus, and in the nucleus, when something like an estrogen binds these nuclear receptors that's directly leading to transcriptional changes, so the genes get turned on or turned off, things like that. Yeah,
Angel Nadal 27:47
exactly. And later, there is one more estrogen receptor that was proposed about 2005 and it's a G protein coupled receptor. Is called GPR. It's at the membrane, and it seems that it binds straight iron as well, and have estrogenic produce estrogenic signaling. I see less study, but yeah, it seems that is also there at the membrane. So we have three layers of resectors and such, and one at the membrane, and they cross talk, so that makes like complicated,
Nick Jikomes 28:33
yeah, yeah. So, you know, estrogen is is flowing through the bloodstream. It can get into cells. It can get all the way through the membrane, into the cell through another membrane, that's the nuclear membrane, and it's going to regulate gene regulate, you know, gene transcription in the nucleus. It can also get through the outer membrane, but not pass through the nuclear membrane, and regulate what certain proteins are doing in the cytoplasm. And there's also potentially, these estrogen receptors on the outer membrane. And so you've got like three interacting levels of control inside individual cells, yeah,
Angel Nadal 29:04
to the same hormone. Yeah.
Nick Jikomes 29:09
And is that, is that special about estrogen, or is that sort of a normal thing when it
Angel Nadal 29:14
comes to sex hormones? Generally, it it's now known that is more it's not only for for, for instance, I would say for asteroid hormones, we can say that. And there are the nuclear receptors act outside the nucleus as well. For androgens, progesterone, vitamin D, as well. And whether there is G protein coupled receptors. That's a different story. Has been proposed for for some but not for other asteroids. Yeah, it is very well accepted. I would say that nuclear receptors act as transcription factors in the nucleus and all. Also outside the nucleus for most of steroids.
Nick Jikomes 30:06
And are most are most tissues in the body sensitive to estrogen to some extent, or is it highly concentrated in a specific subset of tissues?
Angel Nadal 30:18
I would say that all tissues in our body are sensitive to
Nick Jikomes 30:25
estrogens. Yeah, yeah, yeah. I mean, I guess that makes sense, yeah. I guess that makes sense. Because, you know, if you think about something like just the sex hormones in general, they are inside of everyone. They fluctuate across the lifespan. If you think about something like puberty, right, the whole point of puberty is you need to transform all of the tissues in the body in a certain way, and so I guess these hormones are important for initiating that transformation. And it makes sense that, you know, more or less every tissue is going to be sensitive to some extent.
Angel Nadal 30:52
Yeah, yeah. But I think it makes sense. And perhaps there is some tissue that it doesn't have, Sun estuarine receptor or estrogen receptor, but I not aware of it. It is true that this, we have these three receptors, the two nuclear and the GPCR, and it is true that each tissue may have different level of expression, yeah, receptor. You know that that that is true. But as far as I know, most issues spread receptors.
Nick Jikomes 31:27
And I want to talk, start to talk about, you know, endocrine disruption a little bit. I don't know if there's anything you want to set the stage with, but I suppose an endocrine disrupter would just be any exogenous molecule that can affect hormone signaling in an unnatural way, is that a fair basic definition?
Angel Nadal 31:48
Yes, this, I would say, is the definition of the Endocrine Society indeed, is an exogenous chemical which can be natural or or not or artificial, but it affects hormone Axia, that's the more extensive definition of endocrine disruption.
Nick Jikomes 32:13
Yeah. And so how did you, how did you get into this field, and why? Why has this become such an important area of study?
Angel Nadal 32:24
Yeah, when I started, really was, yeah, at the end of of the 90s, when I came to paying back from from England, from London, after my my postdoc and I had to start my own research line. So I was starting, really, my question was, how stradio has a role in adapting the pancreativa cell to pregnancy. So then I, I was at home with my wife, and we were watching TV, and we watch a TV documental that was named assault on the May was a PVC horizon program. And one of these documental and most of the pioneers in the field of endocrine disruptors appear there. And they were explaining, you know, how these endocrine or these chemicals that were acting through nuclear receptors to affect different tissues, of course, nothing about obesity or or diabetes at that time, and because we were using in the lab, stradivale, and see the adaptation of pizza cell using stradivale, why we don't start measuring what happened with this compound called BPA. It's phenolate that, at that time was not so famous as it is. Now you know that that was in 9798 so I tested measuring ion channels, measuring the KTB channel activity with patch clamp technique. So I acutely added Bisphenol A at a very low concentration, one nanomolar, and five minutes after perfusing the cells with Bisphenol A, the channel closes.
Nick Jikomes 34:38
So tiny amount of EPA had a big impact, tiny
Angel Nadal 34:40
amount. This is the amount we have in blood. Oh,
Nick Jikomes 34:44
this is the amount that's in our bloodstream, particularly right now, it
Angel Nadal 34:47
is between one and 18 nanomolar BPA that has been measured, and is more or less the amount of BPA we may have in blood. Yeah. Yeah, and yeah. And then we started, we, you know, that, that that, yeah.
Nick Jikomes 35:07
So you just, you saw this documentary and that that made you want to do an experiment with BPA. And then you got started down this whole
Angel Nadal 35:13
path, yeah, yeah. That was it. So,
Nick Jikomes 35:17
yeah, what? Um, let's explain for people very explicitly, what is BPA and where? Where does it come from? Most commonly, yeah, the
Angel Nadal 35:28
Bisphenol A is one of the main is, is the main component of polycarbonate plastic. So polycarbonate plastic, which is normally transparent. Plastic that we have is hard, for instance, these glasses, this is no glass anymore, is polycarbonate. So this is made by Bisphenol A, and this is the polymer, and is in many epoxy resins. Is in the interior of Canal food. I mean that there is a plastic in there. There's
Nick Jikomes 36:10
a plastic liner in metal canned foods. So most people probably don't even
Angel Nadal 36:14
realize it. Yeah, is made. It contains Bisphenol A, and Bisphenol A is used also as a plasticizer that makes the plastic softer, so you can give a shape to the plastic, etc. Otherwise, the Sun of the polymers are very hard and it's difficult to give a shape and you need to solve the plastic. So BPA sab it for that. So BPA is practically in any plastic, in a way or another. Is in BBC. It's all over, all over, all over. That's one of the problem this, indeed I wanted to be these are recent results from a big European consortium that is called human bio monitoring for EU. They released all the data in the last year. You know, they have been studying the levels of chemicals in the whole European population. And the conclusion is that all Europeans above 18 have BPA in their blood at low doses at least, yeah, but you said really about one nanomolar, yeah.
Nick Jikomes 37:36
So is it safe to assume that virtually everyone listening to this has some amount of BPA in their bloodstream, and it's even if it's a quote, unquote small amount, it's probably a physiologically active amount,
Angel Nadal 37:51
I would say so unfortunately, I would say that more than 90% of the people, they at least in the US and in Europe where it has been measured, yeah, have BPA in blood, probably at a level that affects cells. Yeah.
Nick Jikomes 38:15
So this isn't necessarily a thing where BPA is bad, but you need a very high dose of it, and trace amounts, you know, are probably safe. This is a thing where potentially even low amounts could be problematic, or could be having some physiological impact. Exactly
Angel Nadal 38:31
that we see is that low amounts affect cells, yeah, in particular, insulin release in cells, yeah. And I want
Nick Jikomes 38:41
to dig into that a little bit so you know, from your studies and from what's known in the field, what is BPA? What kind of effects is BPA having with respect to insulin signaling?
Angel Nadal 38:52
Yeah, with BPA, what it does is to first, we can divide in in in two different set of times, let's say acute effect. So if we apply BPA, we very rapidly increase insulin release in a matter of minutes. And this has been study in isolated beta cells from mice, from human as well. And we know that is mediated through the closure of the KTP channel, and it has been also demonstrated in in humans by drinking just one dose of BPA. You know that it affects
Nick Jikomes 39:46
insulin release, yeah? So within minutes, it's already doing something.
Angel Nadal 39:49
Within minutes, it's already doing something, yeah, and later we have done experiments more long lasting, let's say. In vitro, in culture cells during 48 hours exposure to one nanomolar BPA. So they regulate genes. They regulate insulin gene expression, for instance, and they change the context of the insulin the pancreatic beta cells. Increases the content of beta cells, they regulate potassium channels, calcium channels and sodium channels present at the membrane, and also the function of those channels, and they Pro and this is associated with an increase in insulin release. So what BPA does is to produce an over secretion of insulin,
Nick Jikomes 40:42
I see so it's not only immediately affecting the release of insulin, it's also having longer lasting changes that increase the beta cells capacity to release insulin
Angel Nadal 40:52
Exactly. And this is not only in experiments, in in vitro that are very good for understanding the mechanistic insights, but also in in mice. I mean, if we inject with BPA, or we give oral BPA to mice, they get hyperinsulinemia. They get insulin resistance, glucose intolerance, high levels of pre fatty acids, high levels of leptin as well, etc, in adults, males, yeah, and, and then there are other studies done During pregnancy, so we can talk later about that as well. Yeah,
Nick Jikomes 41:42
but I guess on a basic level here, you know, BPA is having a sort of pro insulin effect. It's causing more insulin release. It's doing that immediately, and it's also leading to long lasting cellular changes, such that the cells are basically able to release more insulin more often. And this is obviously going to tend to make it easier to develop things like hyperinsulinemia and insulin resistance. And you know, if I can anticipate where this might go, this would suggest that, you know, let's say, let's say, my great, great grandparents, they were fairly metabolically healthy. They didn't have insulin resistance and things like that. Even if I was eating the same someone today could be eating the same diet, the same nutrients, in terms of fat, carbs and proteins, as say, their great great grandparents. But if their great great grandparents were not exposed to BPAs and other endocrine receptors, but you were living today, you might develop something like insulin resistance and diabetes in response to the exact same diet, because your body is now more predisposed to do it. Yes, I
Angel Nadal 42:48
will say that's correct, indeed. I mean, we have some chemicals, PBA is one example. There are others that affect insulin sensitivity in peripheral tissue, including the skeletal muscle, the liver and the adipocyte, and affect insulin content and insulin release. So are affecting your glucose homeostasis, and then, in response to even the same diet as your grand grandparents, you may have a different control of glucose in your blood. Yeah, that that's true.
Nick Jikomes 43:26
So, yeah, wow. Um, how, how? So when things like type two diabetes and insulin resistance are starting to develop, um, and even when they've developed, you know, considerably, how easy is it for the body to reverse that? If you remove things like BPAs, if you change the diet, like the glucose and the carbohydrate intake, are these states, hyperinsulinemia, insulin resistance, things like this, are they reversible?
Angel Nadal 43:58
Yes, it depends on on the time. I mean, it's a very complex issue. Perhaps we have simplified a little bit just, you know, to make it understandable to be able to understand. But, yeah, I think that the point is, for how long you are having those changes. Yeah, and depending on the time that you are you you have the decrease in insulin sensitivity, or the pancreatic beta cells overworking, or whatever. It depends on how long that it can be reversible or not. So for instance, we have done with adult mice if we inject Bisphenol A during four to seven days, so a week, we get the metabolic changes, and later, we just don't inject for four or five days. And everything is reversible. I see
Nick Jikomes 45:02
in adults, in adults, in adults. So at least at the early stages, it's fairly readily reversible, if it's if it's just starting, yeah,
Angel Nadal 45:12
yeah, yeah, that that, and this is something that happens as well with, for instance, people that is overweight or or obese, and they have a decrease in insulin sensitivity independently of PPE and, you know, and the hyper and so anemia, if they lose weight, even less than 10% of weight loss, improve the metabolic parameters very
Nick Jikomes 45:39
much. So even something like, even something like a less than 10% loss, weight loss can can lead to better insulin sensitivity. Yeah.
Angel Nadal 45:46
And if you start to exercise and and to take care of, you know, the situation a little bit, you can improve. So, yeah, in the case of PPA, in adults, it is reversible. It's something different in the case that during pregnancy, you get an exposure to endocrine disruptor such as BPA or others. During pregnancy, it will affect the fetus and the mothers. And then the effects are long lasting for the situs and for the mothers as well. So
Nick Jikomes 46:28
basically, yeah, if a pregnant woman is exposed to certain endocrine disruptors at certain phases of development, I would imagine, you know, there's certain sensitive periods, this can basically lead to permanent changes that will be, you know, life, lifelong, lasting for the for the baby that's born
Angel Nadal 46:46
exactly, exactly. So that's, I mean, the fetal development is when most genes are, you know, expressing and stopping espresso and kind of stuff, and and then is the most susceptible period for this kind of endocrine disruptors acting through nuclear receptors, You know, to make epigenetic changes, and then uttering the in, you know, gene expression later in life as well, that during the phenotype later in life, does
Nick Jikomes 47:29
BPA or other endocrine disruptors? Do they actually cross the placenta and get directly into the fetal bloodstream?
Angel Nadal 47:35
Yes, yes, indeed, BPA does, and others such as dioxins, they do as well. Most of the lipophilic endocrine disruptors are able to do that. So they plus the placental barrier, and go to the fetus and seeing that there, and
Nick Jikomes 48:00
you said, I think you said that so not only can it lead to permanent, long lasting changes for the developing fetus that will that will go all the way into adulthood, I think you said also that it can lead to long lasting and permanent changes for the mother, so the mother's own endocrine system can be disrupted, such that it sort of doesn't go Back to normal or back to baseline after the pregnancy ends.
Angel Nadal 48:24
Yes. I mean, this is less known that the effects on the fetus, but for instance, during pregnancy, if mice are exposed to endocrine disruptors. So we did it first with BPA. We already published that in 2010 and later have been done with dioxin as well. Then you get that change in the hormones in the mother during pregnancy. So it's not only passing the placental barrier are going to the fetus is that is producing and a change in insulin levels in plasma, leptin levels in plasma, and lipids in the mother, and that changes the environment for the fetus. Yeah. So it's not only the endocrine disruptors passing, but the whole environment in the mother is changing. And later, if, if you study those mothers, as we did, everything goes back to normal during three, four months, and after that, the mothers started to be overweight, insulin resistance, glucose intolerance, they have decreasing beta cell mass, decreasing insulin release from beta cells, and all kind of metabolic alterations in dams. Yeah, wow. And this is, this is pretty new. It needs to be very much studied. That, I think is, is like a new, sensitive window for the mother, for the mother. I mean, yeah, Pregnancy is a very, yeah, plastic period for the mother as well. And, and, you know, I mean, we, we have a project now, that we're going to try to understand what mechanisms are taking place in the mother to to have these long, lasting effects, yeah, appear later. You know, even they disappear and they appear for months afterwards, yeah,
Nick Jikomes 50:39
yeah. And, you know, immediately you wonder, it's difficult not to wonder about common experiences that certain women have with pregnancy. So for example, some women have a child, one or two or three children, say, and they have no trouble, or very little trouble, losing weight and getting back to where they were before the pregnancy and other women struggle with weight gain that doesn't go away, and things like this. And one wonders if this ties into that, if it has something to do with exposure to things like endocrine disruptors like BPA.
Angel Nadal 51:11
Yeah, of course, this is pure speculation, but I mean, what I can say our experiments is that mice that were exposed to BPA during pregnancy, later in life, they were overweight, had these metabolic problems, and we did a control just exposing for the same time, non pregnant females, yeah, we exposed to BPA essentially the Same time, and they had no overweight and no metabolic problems, yeah, this is what I can say. I don't know if that, I mean, we need to Yeah. We don't know if that's actually humans for sure, exactly, but it's a possibility, yeah.
Nick Jikomes 51:54
But basically, what you're saying is think about Yeah. So, so pregnancy is basically, you know, and we're talking about mice here, but, you know, by analogy, it makes sense. This would apply to other mammals. Pregnancy is sort of like it's a critical period in the adult mother. Normally, we think about critical periods of development. We think about childhood and infancy and things like this. But in the adult mother, things are basically more plastic while she's pregnant, because, you know, obviously her, her whole body, you know, needed to, needed to be plastic, needed to rearrange itself in order to accommodate the fetus. And so this can open up the opportunity for long, lasting changes to happen in a pregnant female animal that would not otherwise happen to a non pregnant adult female animal.
Angel Nadal 52:40
Yeah, exactly that, that, that's a very good summary indeed of what I tried to say. Yeah, it's
Nick Jikomes 52:47
Yeah. I mean, it's just, it's fascinating, simultaneously fascinating, but obviously very unsettling. Yeah,
Angel Nadal 52:54
it is scary. I mean, it's always have this mix of feeling, you know, when I see, yeah, yeah, that's true.
Nick Jikomes 53:01
And, you know, I want to ask you about sort of the, you know, you've already said that BPA is pretty potent. Can you say a little bit more about, like, the dose and the potency of BPAs and other xenoestrogens compared to natural estrogens? Are these things generally more potent than natural estrogens? Less potent? How do you start to think about that stuff?
Angel Nadal 53:21
Yeah, I think that's that's a very important question, actually, and one of the main problems that I think we need to still to understand, let's say, for instance, Bisphenol A and other bisphenolS, they have a low affinity for estrogen receptors, about 500 to 1000 or less than estradiol. Got it okay, but they act through these receptors at doses at the same level as estradiol. So let's say the affinity for Bisphenol A of estrogen receptor is within the micromolar range. Yep, but we have effects, we and others. We have effects, 100 pico molar, one nano mole I see, which is far below the affinity of the receptor for
Nick Jikomes 54:28
So technically, by it's acting through other means.
Angel Nadal 54:32
Well, I mean, we are working on that, and, yeah, we are trying to publish a paper in a good journal now. And that we found is that mainly biphenylase acting through estrogen receptors outside the nucleus nuclear receptor, but through the extra nuclear initiated pathway I see, and we do, they do do that. Yes, they have a very high efficacy, because there are ways to amplify the signal. That's one thing, and the other is that there is a proton transfer from the ligand. This is what we are trying to publish some new results now to activate, to switch this extra nuclear pathway. So it's like having a kind of different mechanism to activate this extra nuclear pathway compared to the nuclear pathway, I see, so nuclear pathway is normally has to work with high affinity, yeah, yeah. And outside the nucleus, it can work with a low affinity ligand. I
Nick Jikomes 55:56
see they should have been with a high efficacy, yeah. So the basic idea here, if I'm hearing you correctly, is, so we said before you've got these three levels of control. In terms of the estrogen receptor, you've got intranuclear receptors in the nucleus, you've got receptors in the cytoplasm, on the inside of the outer cell membrane, and then you've got receptors on the outer cell membrane, even though these BPAs might have a lower affinity, a lower stickiness for the receptors than natural estrogens, because you've got these three levels of control, these three different types, these three different flavors of estrogen receptors, the BPAs, might be acting very, very potently at that outer layer, so that they can have strong effects even at A low dose, even though their affinity for the receptor is actually less than the natural estrogens. Yeah,
Angel Nadal 56:45
exactly. It is easier. Well, it is easier if the receptor is outside the nucleus, interacting with other proteins, such as kinases, and then produces second messengers. The signal gets amplified, yeah, and this is something that it doesn't happen in the nucleus, because, yeah, there, of course, is one ligand, one receptor and one estrogen response element in the DNA. Yeah, there is no amplification in that sense. But outside the nucleus, you can interact and produce, for instance, cyclic AMP. And produce many cyclic AMP molecules with just one ligand, you know, and and then have many pKa, yeah, yeah. Activation is validation, etc. So the signal gets amplified, and in addition to that, so we we think that there is another, another switch to activate this extra nuclear effects that it is with BPA that is more kind of a chemical reaction that's only the shape of the molecule inside
Nick Jikomes 58:03
I see. Yeah. So it's like, at these different layers of cellular regulation the signal, the signal can get amplified to different extents. It's sort of like, so you said the nuclear receptors. It's more like a one to one thing. It's like you and I talking here, I could ask you to do me a favor, and I'm just asking on hell to do me a favor. It's one person. But if I go to my balcony and I shout to a group of 10 people, and I can now amplify my signal tenfold, and that's sort of like the the outer, the outer layer of signaling here.
Angel Nadal 58:31
That's a perfect example. Thank you. Yeah, okay,
Nick Jikomes 58:35
but the point, the point is basically, you know, because there's this sort of question that I think some people have, that I've had, when I think about some of this stuff, it's like, okay, we've got all these estrogen receptor these estrogen exogenous estrogens in the environment. The environment seems to be net estrogenic. It's, you know, when we look at sort of coarse grain signals in men and women both, both of them seem to be drifting in the estrogenic direction. But the question in my mind was, well, okay, if we've got these xenoestrogens, but they're actually less sensitive, they're less potent, or they have less affinity for the estrogen receptor. The natural estrogens, they might have a net anti estrogenic effect if they're sort of pushing the natural estrogens out of the way, and they're less potent. But basically what you're saying is that, at least in the case of BPA, because of signal amplification and things like this, they can have a net estrogenic effect. And that makes sense. Yeah,
Angel Nadal 59:28
it may have a net estrogenic effect, but this, it not always does essentially the same as the natural hormone. That's another
Nick Jikomes 59:39
point. Yeah, it's not having the exact same set of effects, not at
Angel Nadal 59:43
all. No, no, no, indeed, because, well, the receptors they need to dimerize, dimerize to to produce, for instance, and they do have homodimers of Australian receptor alpha, homodimers of estrogen receptor beta. A and heterodimerstrogen receptor alpha and beta, okay, and the ligands can make a different pool of these dimers. So we have studied that, and it seems that Bisphenol A doesn't produce heterodimers, but estrogen stradivale produces heterodimers of er alpha and er Vita. So because of the pools of dimers is different between stradion and BPA, that may be a reason to have different signaling. So sand responses are going to be equal between both ligands and some are going to be different. I see, I think that's not exactly the same. Yes, an important point.
Nick Jikomes 1:00:49
Yeah, that is important. So, so the exposure to these, you know, estrogens, it's not, it's not a quantitative change in estrogen signaling. It's not just sort of boosting up or down natural estrogen signaling period. It's a different pattern of signaling and stuff happening in the cell. That's not, you know, not just a different amount of estrogen signaling.
Angel Nadal 1:01:10
Yeah, exactly this is I, how I look it personally. Is okay, really, what BPA and others, you know estrogens is doing is altering, disrupting the estrogen signaling somehow. So it's not really mimicking or antagonizing completely, but is, you know, yeah, it's
Nick Jikomes 1:01:35
truly a disruption.
Angel Nadal 1:01:37
It's a disruption. It's just making a different signal and then modifying the signal for the natural hormone. Because, you know, yeah. Is doing is messing around, yeah.
Nick Jikomes 1:01:50
So obviously, when we think about as you know, it makes sense that we're talking about estrogen signaling in the context of things like pregnancy and early development. But of course, all of these hormones, estrogens, androgens, everything's in males and females. Just, you know, it's in different amounts. There's different patterns of fluctuation at different periods of the life cycle. We talked about pregnancy and fetal development a little bit, but I want to think about how, how these things can affect males versus females now, and it's natural to imagine that the effects would be quite different, because the pattern of estrogen receptors and other things is going to be distinct in males versus females. What do we know about effects in males versus females? For these you know, estrogens like BPA,
Angel Nadal 1:02:35
there is sex differences. This is true. I could say for BPA. And, yeah, the experiment that have been done in the past in terms of glucose homeostasis or obesity, I think the effect that it is with BPA is more in males that in females, it seems that females are protected. But the studies were not really designed to study different insects. But new, new studies have been done, you know, for instance, with dioxins and and it's not a sino estrogen, but it's acting through the arithro carbon receptor, which is another nuclear receptor. And these are results from Jennifer Bruen laboratory in cardista University in Canada. And they show very well how the phenotype in terms of glucose homeostasis, is different between males and females, and they decided the study to see to follow males and females, and it seems that in the case of dioxins, the axion is mostly in females. They have a more dramatic phenotype that mates. And I guess, yeah,
Nick Jikomes 1:04:02
I guess, on a very basic, fundamental level, you know, we would expect there to be a lot of sex differences when it comes to endocrine disruptors, because the differences between the sex, the difference between a male and female, comes from, it has an endocrine origin, right? It's the endocrine system is actually sculpting the bodies differently and making them differentially sensitive to all of these hormones. So we should expect that, I think, right,
Angel Nadal 1:04:23
yeah, indeed. I mean, for instance, in our experiments, we have never seen that phenotype of insulin resistant, glucose intolerance or repair insulinemia in females. So this is why we in non pregnant to do it in in non pregnant females, of course. I mean enough brains or in adults,
Nick Jikomes 1:04:47
so you've got results where BPA exposure in adult males and adult non pregnant females. Yeah, you get, you get bad effects in the males that you don't see in the females. So much we don't
Angel Nadal 1:04:58
see in the females. We didn't publish. The females, we just didn't see anything, and just mentioned place, you know, at that time, like years ago, but other people have done later, you know, these experiments, and it seems that in most of the cases, in off prints, the phenotype is in males and not in females. That has been done with BPA by the group of Rebecca Simons in the Penn university there, yeah, in the States recently, yeah. And in in vitro cells, we we have more or less the same if we measure, for instance, apoptosis in the beta cells we get with Bisphenol A, and we don't get apoptosis with stradivale. And indeed, the stradivale protects one apoptosis by BPA produces apoptosis. Interesting, both. They both use estrogen receptors to do this effect.
Nick Jikomes 1:06:01
Wow. So obviously, yeah, you get different effects in males and females. Not too surprising when we look at, you know, stepping back for a minute, when we look at our modern environment, you know, it's, it seems to clearly be net estrogenic for males and females. I know that at least in the US, the age of puberty keeps getting earlier and earlier for females, then obviously males, it's quite clear, testosterone levels keep going down. Fertility levels keep going down, sperm counts, etc, etc. Why is it so we hear a lot these days about endocrine disruptors and xenoestrogens. We hear a lot about exogenous estrogen based endocrine disruptors. I don't hear a lot about Xeno androgens. Is there something? Why is it that there seem to be so many exogenous estrogens, but not androgens? Is that actually true, or is is there a reason for that?
Angel Nadal 1:06:56
And I think the reason is that mostly estrogen has been studied. And for instance, the effect of sign of these chemicals on androgen receptor is like opposite is like antagonizing. The androgenic effect. For instance, phthalates is a classical example since the 90s that they act as anti androgenic chemicals. I see so they, let's say, decrease their response to androgens, so that's, that's the point, as far as I know. Yeah, I think asteroid and receptors are the most studied. Very likely because they were the first receptors, yeah, to see an effect I
Nick Jikomes 1:07:57
see, but for you know, so basically the estrogen receptor and xenoestrogens, they might just be more studied, which is why a lot of this could be an artifact of where we're focusing our research energy, but the environment still does clearly seem to be net estrogenic. And at least what you're saying when it comes to phthalates is that, you know, even though they're not estrogen disruptors like BPA, they are, they have anti androgenic effects. Yes, indeed,
Angel Nadal 1:08:23
they do. And and we know some of these chemicals, they also affect thyroid signaling, so they they can, perhaps not directly affected the thyroid hormone receptors, but other enzymes that produce thyroid hormone, yeah, and we know that this post came, there are chemicals that can also interact with other nuclear receptors, such as PPR gamma, where tributyltin is one of the main examples, I would say, is cynovesogene as well, and acts as an agonist of PPR gamma. Yeah, there are dioxin, as I said, through the arid locarbon receptor, etc. So,
Nick Jikomes 1:09:21
yeah, so, so two of these other endocrine disruptors, you've mentioned, dioxins and phthalates. Where do those come from in the environment?
Angel Nadal 1:09:30
Well, dioxin is a byproduct of industrial you know, when you bar paper or plastics, or whatever you produce these dioxins. So it's an industrial byproduct, actually, and phthalates are in plastics. It's another microplastic. Is another microplastic. And, and, I mean, it's another chemical in plastics. So phthalates are plasticizers, and there are also in many cosmetics.
Nick Jikomes 1:10:12
So people are putting them onto their skin on purpose. Yeah, yeah. I mean,
Angel Nadal 1:10:16
if China stabilizes, stabilizes perfumes, for instance, oh,
Nick Jikomes 1:10:22
so you could breathe it, you could literally breathe it in, yeah,
Angel Nadal 1:10:26
yeah, yeah, that's, that's how it is, yeah, and yeah. There are really many, many of them of phthalates around, and the other one that is really widespread, and, and is is a problem are perfluorinated compounds which are persistent. They're very difficult to metabolize. They're very difficult to get rid
Nick Jikomes 1:10:50
of them. They don't they don't like break down. They don't get excreted
Angel Nadal 1:10:53
easily at all. So we don't know that there is no much about whether they work through nuclear receptors or not, there are some papers say yes. Others say no, but these perfluorinated compounds are a real problem and and they are also involved in in artery in our metabolisms, they produce obesity and diabetes as well. Yeah,
Nick Jikomes 1:11:20
I want to, I want to talk about obesity. And, you know, energy intake and metabolic rate a little bit. So when we, obviously, we're we live inside of a massive obesity epidemic. Obesity rates have kept going up up and up. And, you know, everyone has their favorite explanation for obesity. Most people think about it in dietary terms. Some people say we're just eating too many calories. Some people say, no, no, no, it's we're eating the wrong calories. It has to do with specific fats or sugars or what have you. But obviously this whole field of study, the endocrine disruption angle, starts getting you thinking about ways that things like obesity and other metabolic syndromes can be induced independent of, you know, the food component, I shouldn't say food components, but the nutritive food components that we eat, you could disrupt the metabolism with some of these chemicals in ways that could lead to something like obesity, even if you know you're eating the same diet as a lean person. What do we know about the effects of BPA or other endocrine disruptors on things like hunger levels, satiety signals in the brain, gut hormones, all of the stuff that we normally think about when we think about food intake.
Angel Nadal 1:12:34
Yeah, well, that's a difficult question. I think, yeah, obesity is the theology of obesity is a very difficult problem, and I will say, is not solved. Nobody really knows why obesity is rising at the way the way it is at the moment, and really how obesity is produced. I think what endocrine disruptors do is to increase our predisposition to be obese. So probably endocrine disruptors are not going to make you obese if you have a diet, you know, with no excess of calories or not too much fructose or pre fatty acids or fat flavor, and you exercise, so you probably are going to keep lean and metabolically healthy. That would depend, of course, of your genetic background as well. So there are multiple factors there, yeah, so, but the point for me is that endocrine disruptors is are one more factor in in the scenario that makes you more predisposed to be obese, yeah. How that can happen? We need to imagine that we are normally exposed to a cocktail of endocrine disruptors, not only to one of them, not only to Bisphenol A. If you are only exposed to Bisphenol A, and it's, for instance, affecting you, your foot intake rate, probably you're going to adapt, and then you're going to
Nick Jikomes 1:14:28
have, yeah, it's easy for the easy for
Angel Nadal 1:14:33
the body, body to adapt, yeah. But we are exposed to about 4050, at least, different chemicals, yeah, in our blood, and they affect every term in the energy balance equation, which is energy storage rate equals energy integrate minus energy output rate. So. Okay, so we know that endocrine disruptors are going to affect energy intake by affecting our hypothalamus. They know that some of them affect the levels of expression of MC four receptors. For instance, in the hypothalamus, we know that they may affect absorption in the intestine. They affect our microbiota, that also, you know, can be involved in in controlling our food intake and society. And at the same time, we know that other chemical DDTs, one good example. Can Affect energy output by affecting thermogenesis in in the brown and post tissue. We know that many of these chemicals affect thy rate hormone, axion and thyroid hormone has, of course, a good relation, I mean, an important relation with metabolism, yeah. And what have been more studies the effect in energy storage, how some of these chemicals affect the adipocytes and they affect adipogenesis and affect lipogenesis as well through nuclear receptors and other mechanism, and promote energy storage. And at the same time as we have been talking about, these chemicals change insulin levels, they change leptin levels, they change adiponectin levels, interlocking levels as well. And you know, it's a whole cocktail of effects disrupting every term and every tissue involved in energy balance equation stop predicting what the output is going to be, what the final phenotype is going to be is very, very difficult, yeah, yeah. I'm sure they they affect and your final phenotype is going to be somehow affected by all the chemicals you are exposed, right? And mostly it seems to promote obesity, diabetes and fatty liver as well,
Nick Jikomes 1:17:31
yeah. And, you know, on one level, it makes perfect sense, right? Like there's, you know, your propensity for obesity has many underlying terms that are going to matter, right? There are certain genetic predispositions. We're all going to be genetically different to some extent. The energy balance equation, as you said, has multiple components. There's the food intake, there's your the energy storage, there are things like energy expenditure and your basal metabolic rate. And all of these variables can be affected to some extent or another by on any number of endocrine disruptors. And so if we're all exposed to a cocktail of these things, and it's a different cocktail for you and me, and maybe I was exposed in the womb, but you were only exposed in adulthood, etc, etc, you know, all of those things are going to matter. And of course, there's there's not just one way to break metabolism and create an obese phenotype. So there's not going to be one singular answer or one singular mechanism for what's causing obesity. Yeah, that's
Angel Nadal 1:18:30
part of the complexity of this field that really we don't have a common mechanism of faxion for all endocrine disruptors. I mean, there are now a list of about 1000 chemicals that are endocrine disruptors, or they may be endocrine disruptors, and we have more than 100,000 chemicals in commerce at the moment, so we don't know many of them, but the effect is, and all these chemicals are going to act very likely through different nuclear receptors, also other receptors at the membrane, or other pathways that we don't know. So that's really a very complex situation, and but this is how it is. This is life, and so this is why we are exposed to a cocktail and affecting, perhaps not too much, but many different pathways, or practically all the pathways that are involved in our metabolism. Yeah, so it is difficult to predict, but it's very likely that this is changing the final phenotype. And see for me, one of the main issues, of course, I work with the insulin, but I mean, it's changing the signals from insulin, leptin and Adi connecting, and all these things. Hormones that tell you the tissues how much you have been eating. So for instance, what we see with Bisphenol A is that you have an over secretion of insulin. So that means you are is like telling your tissues that you are eating more that really you are doing. You know, if you eat something with biphenyl age, you're going to have more insulin release.
Nick Jikomes 1:20:28
Yeah, your body will
Angel Nadal 1:20:30
eat more than you actually did. It's actually you are telling the the adipocyte. So, okay, store more. Yeah, even
Nick Jikomes 1:20:36
though you don't need to store so much, even yourself to store all that fat.
Angel Nadal 1:20:41
It's actually the same to the liver. Yeah, I bet hyper and so anemia promotes insulin resistance, but also fatty liver and also obesity. So you know, changing the the exact levels of those cues, hormonal cues, is really like, I now imagine an example is like changing the time in traffic lights in the middle of a big city like New York or Madrid or Yeah, even for few milliseconds, it would be a disaster. You know, at the very end,
Nick Jikomes 1:21:24
when we think about so, I mean, these micro plastics, these endocrine disruptors, they're in everything we've we've created a world which is filled with these things. And to a large extent, it's unavoidable, unavoidable that we're going to have some level of exposure to these things. What are some of the practical ways people can avoid exposure to things like microplastics and other endocrine disruptors? And in my mind, there's sort of two categories of things I can think of. One, there's things you can do to prevent yourself from being exposed, and we can talk about some of those. But I also want to ask, is there anything that you can do to, anything you can eat, anything you can ingest, that can prevent the microplastics from acting, soaks them up and gets gets them out of your body, or something like that.
Angel Nadal 1:22:12
As far as I know, there is nothing, of course. I mean, we can talk about individual things that we can do to avoid that. But, I mean, there are some studies that are beginning to see whether side effects of the plastic chemicals can be counteract by other fetal estrogens or other, you know, part of diet that you can ingest and just counteract the effect in different type of cells. But as far as I know, is nothing that we can really, you know, advise people to to eat or drink that for you to get drink of, to get rid of those micro plastic or the chemicals in them, the thing we can do is try to avoid eating them as far as we can. So try to avoid, if you can foot in in plastic, if it's possible, because it is not easy. I I know, try to buy organic food as well if you want to get rid of pesticides that we didn't talk about, but they are, of course, also end up in the structures as well. And try to open the windows in your house, this is very easy, and just have pressure between 20 minutes, as we did during the COVID pandemic, just to get rid of the volatile endocrine disruptors that are also in furniture and and in plastics at home.
Nick Jikomes 1:23:55
So the volatile, volatile compounds, well, yeah,
Angel Nadal 1:23:59
yeah, absolutely, yeah. They're everywhere, small concentration, but they do a small effect that, if we add that, then we may have a problem, as we said. So we can do these individual things, but I want to point that really, this is a global problem, and it needs a global solution. This is, this is something that goes in parallel with climate change, in the sense that it's all part of the petro chemical, you know, use for energy and for, you know, Many other components. And the same way that climate change is approached by international entities, the chemical pollution, including the endocrine disruptor pollution, has to be also approached as. As as a global trying to give a global solution as well to to this problem.
Nick Jikomes 1:25:06
What are what are some of the things you guys are working on in the lab today? What are some of the questions related to endocrine disruptors that that you're investigating right now that will probably start to get answers to in the next couple of years? Yeah,
Angel Nadal 1:25:18
at the moment, yeah. We are focused in two different projects. One is related to what we talk about, why bici knows have a high efficacy with low affinity for the receptors.
Nick Jikomes 1:25:38
So even though they don't stick to the receptor, much they are able to turn on the receptor, essentially, quite a bit. Yeah,
Angel Nadal 1:25:45
they turn the receptor on enough time to produce a signal. And this is because there is a proton transfer from the ligand to the ligand binding domain. And we think this is what is switching this extra nuclear axioms. So we're working on that. And we have, as I said, a paper that we are in the last stages of, we hope to publish in the next month. Is already a pre print publish with with this, and we are trying to study that with different ligands and with other and with nuclear receptors other than estrogen receptors, so that that's one of the projects, and the other project, which is together with palomalonso magadena, who is, we are colleagues, collaborating for for many years, is about pregnancy. What are the epigenetic mechanisms that happens in the mother later in life that in order to have this phenotype of Alter glucose. So we we want we know that this phenotype is happening, but we like to understand, what are the what is the mechanism, or are the mechanism driving to those changes in the pancreas, the adipose tissue and the liver? So these are the two projects we are we are involved now,
Nick Jikomes 1:27:23
interesting. How has working in this field changed your life on a personal level? Like, are you, I don't know. Do you still do you? Do you use the same shampoo? Do you use the same body lotion? Has it completely changed all of the products that you're using?
Angel Nadal 1:27:39
No, I haven't changed all of the products, but of course, I mean, I don't exaggerate about this too much of myself, but I take care. I think it is important. So i i Never. I try to eat nothing that is in touch with plastic so I prefer to go to the grocery shop and buy ham or cheese or whatever, and they cut it and give it to me, and not with plastic wrap. You know? Yeah, yeah. I mean these sort of things I don't drink from water. Plastic bottles never so I use, normally a bottle, metal bottle to tap water, to drink feeder tap water. And and with a shampoo, and try to avoid parabens. And as much I as I can read. But this is not easy, yeah, that I try to do is to, for instance, I use solid, solid shampoo to avoid plastic, the plastic bottle, you know. And for shaving, the same, I don't use the plastic shaving batching. So I normally use a metal blade, and it's like the old fashioned, yeah, it is not so nice, you know, to skin, but it works. And I avoid, you know, plastic as much as I can. Yeah, that's all. But I want to emphasize one personal change that I did years ago, because I think the important period to avoid exposure is pregnancy and infancy. Because during pregnancy is when the fetus is going to, you know, have more changes that may last for the whole life. Yeah, so when I had my first child, I didn't know about BP. VA, or the effects they did that was in 96 so we use plastic bottles, polycarbonate, plastic bottles for there. Okay, my second child, we already did the experiments with BPA. He was born in 99 so we avoid all plastic bottles. Later, plastic bottles were banned in Canada, here in Europe, in Japan and many other countries since 2010 2014 more or less, you know, but that that was a personal I think, big change that they recommend
Nick Jikomes 1:30:43
everyone being extra vigilant during those critical periods, just
Angel Nadal 1:30:47
in case, try to avoid exposure as much as you can during pregnancy and infancy, because it's when all muscles of the epigenetic changes are going to happen, and we know that, yeah,
Nick Jikomes 1:31:03
we've covered a lot already. Again, this is, this is a fascinating and terrifying area of study, but obviously very important and relevant to everyone. Are there any final thoughts you want to leave people with, or any things you want to reiterate from our discussion? Yeah,
Angel Nadal 1:31:20
I want to just to say that, as I said, this is a global problem, and I think at least here in Europe, the European Commission is aware of it in the Green Deal for 2030 the European Union, the European Commission, said that we should get rid of toxic chemicals, and we should have zero toxic environment, including endocrine disruptors. I don't know if this is going to happen by 2030, now, the European Union members of the parliament have changed, and we don't know what is going to happen in the next four years. I hope they continue with this, willing in order to fight from you know, in order for our politicians to fight this problem and try to give a global solution here in Europe, and I hope this is somehow translated to other countries, as the states that I know you have different regulation, perhaps no more strict, as we have in Europe. And I was, I want to give this message in the sense, okay, we know that politicians are aware. We scientists work with scientific societies. For instance, The Endocrine Society and the European Society of Endocrinology are working very much with policy makers trying to decrease at least this problem, decrease exposure to independent disruptors, and to change policy making to avoid what we just been talking about. And yeah, I want just to give these messages, that is going very slowly, but I hope it continues, and one day, I don't know if I will see it, but we have really zero toxic chemical environment, all
Nick Jikomes 1:33:41
right. Well, Professor on hell Nadal, thank you very much for your time. This was fascinating.
Angel Nadal 1:33:46
Thank you very much. Nick have been my great pleasure talking to you.
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