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00:02
Hey everyone, it's Mikki here. You're listening to Mikkipedia, and this week on the podcast, I speak to Dr. Paul Reynolds. Paul and I talk about the effects of vaping on health, particularly its impact on inflammation, cancer risk, and pregnancy outcomes. Super interesting conversation. So, Dr. Reynolds, whose background is in lung development and disease, has been investigating how e-cigarettes influence

00:32
glycation and long-term health risks and he defines what he means by glycation. We go into that in great depth. And in this conversation, we discuss why breathing is just more than just taking in oxygen and how air quality plays a critical role in overall health.

00:49
As I mentioned, he explains glycation, how it damages the body, and how inflammation, often seen as a necessary defense mechanism, can sometimes do more harm than good. And I know that that will not be news to anyone who listens to this podcast. So we delve into the chemicals found in e-cigarettes, comparing their inflammatory effects to traditional cigarettes. We explore whether vaping genuinely helps smokers quit or if it fosters new dependencies, as well as the risks of second-hand exposure.

01:18
exposure and how vaping should be approached from a public health perspective. Dr. Reynolds also shares findings from his research on vaping during pregnancy, including its effects on fetal and placental weight and the potential implications for conditions like intrauterine growth restriction and preeclampsia. Finally, we discuss how e-cigarette flavors can influence cancer cell invasion and inflammation.

01:45
raising questions about whether some flavouring compounds should be restricted. With vaping still largely unregulated in many areas, Dr. Reynolds offers insights into where research should focus next, what policy makers need to consider, and whether vaping should be treated with the same caution as smoking. So I think in light of the increasing prevalence of vaping and

02:09
I guess policy initiatives around it, this is a must-listen for anyone interested in the science of vaping and its potential long-term health consequences. I think you're really gonna love this conversation. So Dr. Paul Reynolds is a professor in the Department of Cell Biology and Physiology at Brigham Young University, with a research focus on lung development, pulmonary disease, and the effects of environmental exposure such as tobacco and vaping aerosols on respiratory health.

02:37
He holds a PhD in developmental and molecular biology from the University of Cincinnati and has conducted extensive research on pulmonary injury, oxidative stress, and inflammatory pathways. His work examines how vaping impacts lung function, fetal development, and cancer progression, with recent studies exploring the role of e-cigarette flavors and nicotine in inflammation and disease risk, as we talk about today.

03:04
Dr. Reynolds has received multiple awards for his research and teaching, including the Parker B. Francis Fellowship in Pulmonary Research, and is an active member of organizations such as the American Physiology Society and the American Thoracic Society. And he's genuinely such a great guy to listen to. So I was really pleased to be able to get the opportunity to really talk one on one with someone who is like leading the field of research in this emerging area.

03:33
Before we crack on into the interview though, I would like to remind you that the best way to support this podcast is to hit the subscribe button on your favorite podcast listening platform because that increases the visibility of Micopedia and it might literally thousands of other podcasts out there. So more people get the opportunity to learn from the guests that I have on the show, including Dr. Paul Reynolds. All right, team, enjoy this conversation.

04:02
So Paul, thank you so much for your time this morning. I really appreciate it as we were just chatting about, this is such an emerging area of interest in public health, but also just the general public, right? Want to really understand better the risks associated with vaping as they pertain to vaping themselves, and also how they compare to smoking. So, I mean, your background was initially in the area of lung development and disease. So a bit of 101, really.

04:31
Why is breathing more than just taking in oxygen? And a follow-up question to that is, how does air quality impact our health? No, those are great questions. Thanks for giving me a chance to kind of introduce myself, at least kind of the history of where I'm coming from and what we're all about currently. You know, in my training, my background is really fostered by some experience in this idea of breathing. And...

04:56
inherent interest really, you know, breathing is one of our most automatic yet essential functions, right? We can, I'm imagining all the birthday candles I'll have to blow out this year. Oh boy. And there's, you know, we can take a big, deep breath in, we can consciously hold that breath, release it as needed. I can go swimming, all these types of voluntary things. But the moment I focus on something else, there's that automatic aspect that kicks in.

05:19
And what I've been interested in for so many years is the idea that so many people just don't realize that the quality of air that we breathe or we inhale can affect really everything from our energy levels, our chronic disease risk, and those types of things. So my focus historically has been on, for sure, the trafficking appropriately of oxygen and CO2. That's, you know, physiology 101 stuff. But more importantly, I've been interested in those fine particulates that are...

05:48
unfortunately abundantly available and also can cause problems. So these particulates are really tiny, they're invisible pollution that floats around and they're so small they can get deep into our lungs but beyond that they can even enter into the bloodstream and that's a problem. Yeah, Paul, this is a bit of a tangent really but I remember seeing either graphs of life expectancy or quality of life of people that live in metropolitan areas.

06:14
areas where the air quality is lower. Is there a strong association between where we live in the air quality and the sort of mortality morbidity? There is, absolutely. And from a metabolic standpoint, that's very clear, right? If you look at folks that live in areas that are heavily polluted, they're overweight more often, they're more prone to diabetes, lots of different metabolic consequences. But, you know, just to kind of...

06:41
add some doomsday to our story. You know, living on this planet, unfortunately, once we reach about the age of 20 or so, our lungs are on a steady decline, unfortunately. There's simplification that happens, breakdown of the tissue, most of that's elastin. In fact, if we were to live to be about 120 or so years of age, we're going to die, all of us die of emphysema because our lungs simplify. About a percent of our high, you know, kind of lung volume is lost every year or so from age 20 beyond.

07:10
Now our Western diet, our lack of exercise, all these other culprits will probably get us before then, but all these are hits that we have to grapple with. So basically age in itself, the aging tissue declines to the point where if nothing else happened to us ever and we were like the Brian Johnson's like never die type thing, we would probably still die with emphysema. That's right. Our lungs are chronically simplified over time.

07:38
And the goal now is to just avoid as many hits as possible. So you've alluded to folks that live in polluted areas. These fine particulates that I've been focused on for many years are those things that come from vehicular exhaust, wildfires, cooking smoke, fine dust. Even the microplastics, most of those are ingested, but there are also some respirable microplastics. And again, these particles are so small, the body just can't filter them out very well.

08:06
And that makes it particularly dangerous, especially in the lungs. You know, that's the point where they'll interact with tissue first, but the heart, metabolically active tissues, lots of tissues in the body will eventually see those particles. You know, Paul, I've heard a lot about microplastics and sort of part, and the things that we're talking about, the air quality stuff. And I get a sense that some people hear this and they dismiss it as being sensationalist, like, oh, here's just one more thing that we need to worry about.

08:35
I think about it like, we just know so much more now about this stuff. I guess to what extent do people need to take it seriously? Well, when you think about lungs generally, for instance, let me just back up a bit and just mention that as either clinicians or researchers, we have this kind of nature, if you will, to focus on our areas of expertise or interest as being...

08:59
distinct entities, totally siloed and different from everything else. But we know so much more today than we ever have about how the lungs are directly connected, for instance, to metabolism and the myriad systemic diseases that we grapple with today. Right? There's a general conclusion that the things that we eat, we've known that for a long time, and now the things that we breathe can make us sick. And hopefully, maybe later we'll have some chance to talk about glycation, but that's one of the main unifying themes

09:28
things that we eat and the things that we breathe. But I'm with you. You've got a lot of people that might say, hey, there's not much I can do about this. I'm here on this planet. It's not as clean as we'd like it to be, and I'm breathing all the time. That's true, but steps can be taken to help mitigate as best as possible. Exercising indoors on bad air quality days, that's one thing, but it's the multiple hit hypothesis that might encourage us to make some adjustments.

09:55
Yeah, nice one. And you mentioned glycation. And you mentioned to me over an email that the things that we breathe and the things that we eat can cause glycation. So, can you just define what that is and explain the damage that it does in the body? Yeah, absolutely. That'd be great. So, this kind of, again, rewinding the clock a bit in terms of my career, I've been focused on

10:25
But, and again, that stems from this fine particulate stuff that we've been talking about. Fine particulates, yes, compromise lung physiology, but they do so much more than that. They cause systemic inflammation, oxidative stress, and they also can mimic this idea of glycation. So, let's talk about that for a bit. Glycation is the process by which excess sugars bind to proteins and fats and DNA. Sugars are sticky. There's some interesting chemistry in play for those of...

10:54
your listeners that are interested. It's mostly considered Malliard chemistry and Amidori rearrangement. Lots of chemistry trauma may be elicited in the lives of some of your listeners hearing that. But these little sticky particles, these sugar molecules will stick onto any molecule protein, fat and DNA and they'll form what's called an age, AGE. Those are advanced glycation in products. But importantly, notice I mentioned the excess ideas. So,

11:23
I like to think of glucose as one of, you know, pursuing one of three main paths, right? So when we sniff out glucose in the body, first thing that we'll often do is we'll burn it up and get the energy, right? This is all the glycolysis stuff. This is the Krebs cycle or the citric acid cycle, right? You're going to massage this energy-rich molecule and generate ATP. So that's number one. The second thing that we'll do with glucose generally is we'll store it.

11:50
You're getting ready to go on a fast, you've gone without nourishment for a period of time. So there are certain tissues in the body that are better than others, but some areas will store glucose against the rainy day type of thing. It's the third thing that's underappreciated, I think. Anything beyond what we burn up, what we store and lose in our urine, we then will use for glycation. And these ages, the sticky sugar that's everywhere will accelerate aging, it stiffens arteries,

12:20
They've been definitely implicated in worsening things like diabetes, heart disease, and Alzheimer's disease. But it's basically best thought of as, you know, glycation is where sugar sticks to things in the body where it shouldn't. Okay. And as you mentioned, the glycation, I think of hemoglobin A1C or HbA1C. So that's, is that the, explain what that is and how that relates, if that relates.

12:47
Oh, it definitely does. And in fact, that's probably the thing that most in your audience and others would recognize. HbA1c is hemoglobin. A1c identifies a part on hemoglobin that's highly prone to glycation. So I like to sometimes teach our undergraduate students, glycation is similar to kind of getting syrup stuck on your fingers, right? Your fingers still work. They do whatever the jobs they need to do, but they're sticky, right? They just don't work as well and you're annoyed.

13:14
What doctors will do in a clinical setting is evaluate a patient's hemoglobin A1C or A1C level. And that's essentially the long-term glycation damage specifically on hemoglobin. So red blood cells live for about three or so months. Any patient could immediately get an assessment of their blood glucose levels by looking at their continuous glucose monitor, the CGM. That's a snapshot of what's happening right then and there.

13:44
But what A1C levels suggest is the long term, you know, over multiple months, the relative amounts of sugar in the blood. You know, it doesn't really encapsulate the excursions that some people take, you know, when they hit the carbs hard or they don't. But more importantly, I think, Nikki, is the idea that A1C is an important indicator of what glycation is in the body, but it should never be viewed as the only protein that's glycated.

14:13
There are not good tests for albumin, for instance, or insulin, or any other protein in the body, but please know that if you have a high A1C level, all proteins are also glycated. So all of them are struggling a bit to do their normal job. Yeah. Okay. That's super interesting, Paul. So can we, if you, obviously you mentioned inflammation as a companion of glycation and everyone listening will be familiar with the idea that excess inflammation isn't good.

14:41
for ourselves, but can you sort of just chat a little bit about that relationship as it pertains to glycation and then we'll sort of move on to vaping, et cetera? Yeah, no, that sounds great. So inflammation, as everyone really knows, is kind of our body's natural defense mechanism, right? Any perceived threat will be responded to via some form of inflammation.

15:05
So I like to think of it, you know, as your body's built in alarm system, your immune system responds to injuries, infections, those types of things. If you cut your finger, for instance, there'd be a place that gets red and swollen and warm. That's wonderful news. That means your body's working to heal itself. But in cases where that same pathway becomes more chronic, long-term, doesn't abate, that's the condition that we want to avoid, right? This long-term inflammatory reaction is what, you know, instead of healing...

15:35
it starts to damage healthy cells, healthy tissues, and healthy organs. Obviously, we know, you know, poor diet, stress, lack of sleep, those types of things contribute. But one thing I'd like for your listeners to know is that glycation is that insidious process that leaks, you know, kind of lurks in the background. But what's cool is that this age product doesn't just float around and do nothing. It rather will interact with the receptor for ages. That's called rage. Not the emotion, but...

16:05
The receptor for ages are the receptor that's bound to the cell, it recognizes these age products and then inside the cell, it ramps up inflammation like crazy. So that is a focus that I've had in the lung for so many years, but now that I've kind of expanded my view in the last decade or so, I found that diesel particulates, those are small combusted, you know, fuel-based particulates abundantly available in the atmosphere.

16:34
They never settle. They're so small. They're just everywhere. Those will interact with the RAGE receptor. Vaping constituents, we'll talk about that in a bit. Those also recognize RAGE receptors. All these glycation products are also those that can recognize the receptor. So unfortunately, this receptor is unlike pretty much all other receptors in that it kind of recognizes specific geometry, right? It's variable, has a variable domain. So...

17:03
Unlike insulin that binds insulin receptor and only that receptor, rage can bind a whole host of different things and cause some problems. That is usually inflammation. Okay. Interesting, Paul. So can we, with all of that in mind, let's move on to e-cigarettes, vaping, et cetera, because they're often used as a substitute for cigarettes. There's a real...

17:28
Maybe not an argument, but there are discussion points that these are a better alternative, which some people will read as these aren't that harmful in comparison. What are the primary chemicals in e-cigarettes that may cause harm, that might actually turn on its head the argument that vaping is not harmful? No, absolutely. That's a great comment because, again, these are products that are billed as safe alternatives

17:58
You know, we've all had a grandma that smokes. You don't want to do that. That's crazy, right? So unfortunately, that theory is out there, and that is supported by too many. So if we can maybe start from the beginning, basically the mechanism of mods, those are the modified e-cigarette delivery systems, or any type of an e-cigarette system, involves the superheating of a liquid. That's called the e-liquid. And the reason you do that is you want to produce an aerosol. And that aerosol is then inhaled by the user. Here's how it works.

18:28
First off, there's a heating element. Some will call that the atomizer. A battery will power a metal coil, heat it up so much that that liquid becomes vaporized. Unfortunately, there's some control that the user can use to their advantage. The temperature and the power can be adjusted upward to give more aerosolization. And the problem with that is you're going to increase the toxin exposure, some of that to come.

18:56
The second thing in addition to the heating element is the e-liquid cartridge or the tank. In that little reservoir, you'll typically have nicotine, which is one of the main components, but then there's a whole host of different additives that will make delivery more efficient in theory. Those include propylene glycol, vegetable glycerin, and a whole host of different flavoring agents.

19:21
The problem is when you mix all this into this big cocktail and the mod then with, again, the user that's customizing the aerosolization, you have, yes, increased nicotine delivery, but so many other chemicals that we can talk about. Yeah. Paul, does the heating of that liquid cause in itself some sort of additional harm? It does, right? Because again, this isn't just a singular cigarette that someone would smoke and, oh, I'm all done.

19:51
I'll take a break for a while. This is a reservoir that can be quite thick, so you can be vaping continuously for many, many hours without interruption. So here's what some of those chemicals become. Nicotine, when superheated, has a tendency to go to nitrosimation. So that's where nicotine-derived nitrosamines are made. Those are carcinogenic. Obviously, the nicotine people want to feed their addiction.

20:17
but there are some carcinogenic compounds generated when it's superheated. So that's a problem. Cancer causing cardiovascular disease, worsening those types of things. The propylene glycol, when you superheat that, it causes the formation of formaldehyde and acetyl aldehyde. These are also toxic. Aldehydes cause lung irritation on the front end, but also can over time remodel the airway completely. They're also carcinogenic, right? So bad, obviously.

20:46
The glycerin, this makes a particle known as a creolin. Initially in small amounts, that's a lung irritant, damages the airways, elicits inflammation through the same rage pathway, but a more chronic use and there's studies out there that show even after just a few months, major respiratory diseases can result. So those are some of the things. Obviously, the flavoring is so dynamic. There's so many different agents out there. But most of those will, when superheated...

21:15
form a molecule known as diacetyl or benzoylaldehyde. And these are kind of linked to the popcorn lung, bronchial obliterans, if you will. And it's an irritant generally, but again, the levels are so high because people are assuming, hey, I'm not smoking, I'm not inhaling combusted particles of a tobacco plant. This is mist or this is just vapor, it's totally fine. But all these small carcinogens, together with the heavy metals,

21:44
lead to some major, major problems. So people vape as a substitute for smoking because it has that same action of inhalation, whereas other people might have a nicotine patch and actually be protected somewhat from a lot of the things that you've just described, well, most of them actually. Yeah. No, that's totally true. So if you were to contrast the two, yeah, they are disparate in some of their...

22:11
modalities of delivery, but there are many of the same conditions that are encountered, especially when you're doing the inhalation aspect like you've mentioned. Yeah, that's crazy. So Paul, how do these, I mean, there sounds like quite a few nasty things that you're sort of inhaling with the vaping. How does it compare to just smoking traditional cigarettes? Like obviously there are going to be vast differences, but can we grade them on levels of harm? I mean...

22:41
It makes sense to me that smoking would be way more harmful, but what you're describing doesn't actually sound that great either. Yeah. There's definitely not a safe alternative to doing some of these behaviors with, again, the notion that most people are just looking for nicotine delivery. Most people are looking for the addiction to be fed. But if you were to compare the two, maybe for some users, there's a preference for one. I think there is a bit of a gradation that we could discover.

23:09
But compared to traditional cigarettes, e-cigarette chemicals are marketed as a trigger that causes lower inflammatory responses. I think excessive inflammation generally is not a good idea, especially when you consider, the data suggests that there's a lot of people that shift from traditional smoking toward a vaping type modality in hopes of quitting, but very few do. They're not completely harmless and the addiction still feeds.

23:38
exploration of different flavorings and different kinds of things that are true problems. But while traditional cigarettes produce thousands of toxic chemicals, many of which do cause strong inflammatory reactions in the lung, bloodstream and tissues, e-cigarettes still combine or contain abundant toxicants as well that produce inflammation. And that same thing can have some chronic aspects as well. Yeah.

24:08
You mentioned earlier that people who smoke would smoke a cigarette, put it out, and then a lot of people might just wait a little while and then want to feed that addiction again. Whereas vaping, it seems you're right, people are carrying it around with them all of the time and it's habitual, it appears to be habitual just to take it. So you'd have to know how often people were actually inhaling in order to get a really good clear understanding of the level of harm.

24:36
Yeah, absolutely. And in fact, although these are somewhat ancillary in nature, some kind of correlational studies, which I usually frown at, I don't look for those generally, they're not as valid as like the true mechanistic research, but there are some evidences out there that because of that intuitive, hey, this is not as bad, I'm not going to do it as much, they still succumb and they give in and they do it so repeatedly that it does cause major lung inflammatory diseases. Here's one example.

25:06
You may have heard of this handful of years ago, there's a disease now coined EVALI. That's the electronic cigarette or e-cigarette or vaping assisted lung injury. And this is an acute issue first off, but it does lead to severe lung inflammation. What the data show is that it's linked to vitamin E acetate. That's found in a lot of the vape products at the time. Symptoms of course are shortness of breath, chest pain, fever, coughing, you know, basic stuff that folks endure.

25:36
But there was a spike several years ago where there were major hospitalizations and even death in many cases. This Evali outbreak, it was common in America in September 2019. In that month alone, there were 2,800 hospitalizations and 68 deaths in America, all related to this vaping idea. The surge was, again, linked to THC-containing vaping products. So people were looking for multiple, again, modalities to feed addiction.

26:05
and usually the THC is adulterated with vitamin E acetate. I mentioned that's kind of a cutting agent. But, you know, with this huge outbreak, you know, there were some public health interventions, increased awareness. So the number of the valid cases actually declined significantly the following year, but they're still sporadic cases today, right? That have, that continue to emerge, you know, four years later in 2023 at the American College of Chest Physicians, their annual meeting, they highlighted...

26:33
highlighted the main trend that came from this new disease, this Ivali disease. Children younger than ever before were being hospitalized with lung disease, similar to acute lung injury. And while the epidemic waned a bit, the numbers weren't quite what they were in September, the condition still remains a public health concern. So got to get the word out. Yeah, crazy.

26:58
uptake of vaping where you are? Like where I sit here in New Zealand, in Auckland, I see a number of kids with vapes, like kids who are at school age, kids vaping. Absolutely. Is that the case for you? And do we have an idea of prevalence? Yeah. So there's some data. Obviously, it varies from region to region, right? There are different parts of the country that are not as susceptible or at least not as rampant. But there are some...

27:26
Data that suggests that up to 40% of adolescents have tried vaping in America. Many of those are, again, this new cohort of nicotine users that will not be able to shake the habit very well. Unfortunately, those types of incidence rate type data are sporadic at best, so we definitely need to look at more into it. The problem is the outcomes of vaping often lag the identification of vaping as a cause.

27:56
chronic irritation, feeding toward inflammation. Part of that is through the rage glycation pathway, but there are some other parallel ones. The end is, again, bronchitis and airway inflammation. That's the same thing that patients present with when they have COPD. Popcorn lung, I've mentioned, is very closely related to diacetyl. That's one of the main ingredients of some of the flavors.

28:24
generates diacetyl quite easily. The irritants in vaping, as they increase inflammation, they worsen asthma and make allergic lung conditions worse. Immune responses are compromised. While there are probably primary causes of all of those anomalies I've just mentioned, obviously COPD with primary smoking, asthma with predisposition or other irritants, those types of things have primary causes.

28:54
vaping is always going to worsen those outcomes. Yeah. And Paul, is there any genuinely safe way to vape? Or any use case for vaping as you sit there in your, with this knowledge? I've not come across much data that supports a safe way to do it. Unfortunately, we're fighting against public service announcements and other kind of marketing approaches that say

29:23
vaping is a safer alternative to traditional tobacco smoke. I think if you do some N of one studies, meaning you got someone that is smoking a pack a day and they go to vaping only a few minutes a day, yeah, you're definitely improving. The burden you're placing your lungs in is an improvement. So I think a case could be made on an individual basis that there's some improvement afforded by this new way to deliver nicotine.

29:52
But again, the preponderance of the folks that are using vaping are just not that way. They're going to say, hey, this is not as bad. I'm going to hit this thing all day long. And that's where they have, again, the multiple hit issue work to their disadvantage. Yeah. And you've mentioned several times about the problems that the flavorings sort of present as well. Like, do non-flavored vapes exist or do people not really that interested in that?

30:20
I think they do. But again, if you were to look at some data, marketing data on who's buying what, menthol is really big nowadays. And there's a push here in America to kind of sideline its availability. But I don't have the numbers in front of me. I think some people might try the non-flavored versions. But unlike the ashtray mouth, why not go for the minty or the cinnamon flavored stuff, right? So people-

30:48
people are definitely shifting more toward that preference. Yeah, here in New Zealand, actually, I think this was a few months ago, I saw it in the newspaper that one of the recommendations from the government was to allow free access to vaping or discounted access as part of our Quitline initiative. Do you have any thoughts on that as a public health policy? Well, that's an issue. See, the problem with some health,

31:18
policy. And let me just share my personal opinion here for just a moment. I'm definitely in the camp that allows for personal freedom, freedom of choice, do what suits you fine. But there's a balance to that, right? You can't allow things with that have a known problem to fester. And the issue with public policy is that often those decision makers wait until there's such an avalanche of negative outcomes.

31:44
So then they're kind of a lagging indicator and they say, hey, we probably shouldn't do this. You know, this thalidomide is probably not a good idea, but we waited until so many kids in Europe, it was more of a European problem, were born without the arms, right? So I think there's a role to play for sure in policy. And I just really advocate for folks looking at all of the data, not just a better than worse than, but really look at the outcomes and make informed decisions. Yeah, that's such a good call.

32:14
Paul, I know that you've looked at some – you've looked at pregnancy outcomes and vaping, actually. So can you chat a little bit about what you were looking for in that research and your major findings? Yeah, no, that'd be great. Thanks for asking about that. Let me just start by saying that all of the research that we've been doing have been conducted in mouse models, right? So we have many different mouse models of various pregnancy complications.

32:44
And while we have not observed these types of outcomes in the human specific context, others have. So what we've found are things that are supported by research conducted by others. What we found is that in response to vaping of these pregnant animals, they have lower placental weights by and large. And they also have...

33:11
lower fetal weight. So the actual weight of their pups, if you will, is quite a bit lower. Now, that's in comparison to non-exposed controls. So everything else is controlled well, right? They're all the same age, they're the same sex. We don't see any sex unique differences. But we know that these complications are occurring. Now, your audience would know, of course, that the placenta is critical for delivering oxygen and nutrients to the baby. So any disruption to the placental weight can impact...

33:39
by extension the fetal weight, the organs that develop within the fetus and also long-term health. There's this idea that there are antenatal issues. Those are problems that happen during embryogenesis and fetal life that can set the stage for issues that emerge even decades later in the human condition. In fact, I'm reminded of a bunch of data that have come out recently showing that the incidence rates of COPD is quite a bit.

34:08
more prevalent in those that were, while gestating, exposed to tobacco smoke. Now, those long-term 40, 50, 60-year-old studies did not exist until recently, but there is that connection. Yeah. Are there any genetic links here, Paul, as to make some people more susceptible to the damage that we're talking about, both sort of personally, but also in the pregnancy outcome data?

34:35
I think there are. It's just that that area is just so novel that there's not really a clear handle on what those genes might be. We just received a grant from the National Institutes of Health just a few months ago. You mentioned Ben Beckman. Ben Beckman is a co-investigator on this grant as well as Dr. Juan Arroyo. He's an expert in placenta development. So the three of us worked together to kind of check the boxes of the metabolic impact of vaping.

35:05
during gestation with Dr. Arroyo's input, and all of that, of course, is through a pulmonary axis. So, our focus here is to understand the consequences of exposure by teasing out specific genetic programs. And it's all coming back down again to this rage idea, right? Nicotine and toxic chemicals and e-cigarettes can impair the placental function, but we've newly discovered the receptor for glycation products in the placenta.

35:33
We found those same receptors in fat cells and muscle cells. So if you've got these ultrafine particles that jump into the body via inhalation, are so small, they are allowed to get into the bloodstream, they'll travel to these distant lands, if you will, within the body and cause these same inflammatory outcomes. Real risks for fetal development. People might think, well, come on, Paul, you did your research in rats and mice. I mean, how applicable is it to...

36:01
humans, albeit your research is aligned with your colleagues in another research unit who have also seen these same outcomes. So there is clear parallels between what we find in rodents versus human when it comes to pregnancy? Absolutely. Yeah, they are great models. In fact, they're well represented. We have a few models, for instance, that focus on intrauterine growth restriction.

36:29
We may talk about that a bit later. Another set of models that focus on preeclampsia. So, you know, there's this burden that must be met in order to evaluate these types of outcomes in gals that are pregnant that are also vaping, right? Those folks are discoverable, but they're also hard to come by, right? So we wanna be careful ethically to evaluate those in the best way. Yeah, and you mentioned, as you mentioned, preeclampsia.

36:58
intrauterine growth restriction, vaping contributes to these? Absolutely. Yeah. So let's talk about those if you got a few minutes on that one. So intrauterine growth restriction is basically a condition where the fetus does not grow at the expected rate that should grow during pregnancy. And therefore, they have lower birth weight and the potential for some developmental issues.

37:23
or intrauterine growth restriction is when the placenta fails to deliver enough oxygen and nutrients. And that could be because of poor maternal blood flow, nicotine exposure is very clearly indicated in those conditions. And also just some general genetic placental non-dysfunction, if you will. So, IUGR will increase a woman's risk of having a stillbirth delivery, preterm birth, kind of an intermediate aspect, if you will. But again,

37:52
IUGR babies have more likely, more higher incidences of respiratory problems, long-term health issues like heart disease, diabetes, those types of things. So when you think of it in the context of vaping only, for sure tobacco smoke causes IUGR among other things, but vaping in our hands does as well. Here are three main areas that kind of are associated with IUGR. First off, nicotine is known as a vasoconstrictor.

38:22
tighten up, if you will, blood vessels. And when you constrict blood vessels, you know, reducing utero placental blood flow, that can limit oxygen and nutrient delivery. I think that outcome is more of a secondary effect, but it's definitely modulated to some degree by nicotine. Another area generally is placental dysfunction, right? Anytime you expose a woman to harmful chemicals, especially those same types of chemicals we find in e-cigarettes,

38:50
you can have insufficiency of the placenta. It just doesn't grow as well. It doesn't invade. We often, I teach an embryology class on campus here and we talk about how women have this really nice nine-month parasite. Thankfully, there's an end to that. And at the end, you know, you got a nice bouncing baby boy or girl. But when you have placental insufficiency, the invasion of that placental tissue, usually it's the villi that get into the endometrium.

39:19
That's just compromised by the chemicals as well. The last one might be oxidative stress and DNA damage. E-cigarettes are rich in those types of agents that cause oxidative stress. Those are free radicals and those are very known causes of DNA damage. I like to sometimes think of free radicals as kind of disobedient children. These are the little troublemakers that have been damaged a bit where they're missing an electron.

39:48
But they don't just hang out and pout about that. They run around and try to steal an electron from someone else, causing those molecules or those other kids to misbehave later. So all of that is one of the big keys, sets of keys for IUGR. Yeah, interesting. And I was just thinking about what you were saying regarding the metabolic health outcomes of the little human. So in addition, of course, to heart disease and diabetes, obesity, and all of that might

40:18
also be more predisposed to experiencing through the changes in the DNA? Absolutely. Absolutely. In fact, I always want to contextualize it with this backdrop of location. Carbohydrate restriction will help in that regard, but keep in mind the liver is dynamic. We love the liver. It does so many wonderful things for us, including ensuring adequate glucose levels. So we're going to have baseline glucose no matter what we do.

40:46
But it's those excursions that cause more glycation that then will impact not just the lungs or tissues that are encountered through the bloodstream, but so many other outcomes as well. There's a role for glycation in diabetes, in skin health and aging, right? The wrinkles and sagging, loss of radiance, all of that's directly related to things that occur as glycation proceeds when we age, essentially.

41:14
Alzheimer's disease, heart health, gut health, all of those types of things are, you know, again, there's some primary causes that compromise those tissues, but glycation, even the glycation that happens as a byproduct of vaping will worsen some of those healthy aspects. Yeah. And, you know, I think like my mother smoked with us when she was pregnant. And I can't recall whether her mother smoked with her. And she gave up.

41:42
maybe when I was a teenager or something like that. She sort of fake gave up and then gave up for real. But she has a gene that predisposes her, a gene to do with her lungs actually, Paul. And she got tested for it because she's actually got COPD. And she wanted to, and she's like, you guys have to get tested for this gene to see whether you're more at risk of these things. And I'm like, well, I don't know that I necessarily need to get the gene test because I don't smoke, I don't vape.

42:11
Am I at a higher risk of, this is sort of unrelated to vaping really, but a higher risk of poor lung health because of her smoking throughout her pregnancy with us? Well, there really has to be a threshold that's met for that to manifest well. Like I mentioned, there were some of those studies that focused on over 60 and 70 years, folks that were incubated, if you will, in utero by a mom that smoked or a mom that was exposed to secondhand smoke.

42:41
and then trying to track the health outcomes of the offspring over that period of time. So there are some connections there. But again, there's so much that could be done with regard to incorporating better habits post-birth, right? That can lead you on a more healthy path. The healthier you eat, the healthier you are based on your exercise routine. Those types of things can minimize some of the hits that you may have had early on and you can overcome them.

43:09
I will mention that from the IUGR point of view, yes, low fetal weight and some other issues are a burden. But what the data show is that usually by the time those humans are at adolescent age, they've recovered as far as body weight, those types of things. So they do catch up. It's just that again, the hidden kind of cost of being so premature from an early point of view into the future, we need to look at.

43:36
reminded earlier in our conversation, you were talking about multiple hits, and that's actually the multiple exposures. So, poor four parents. I wonder, actually, whether we have any data or any sense of the, not just maternal, sort of vaping and how that might affect the fetus, but what about dads? Does that have any impact on sperm? I mean, I'm not sure if you know this, that then might also impact on...

44:04
on pregnancy outcomes? That's a great question. And that's actually one of the aims of this recently funded grant that we got from the NIH is to look at the modulation of sperm. We've already published a few times that focused on this idea that epigenetically sperm is modified. That's where there's some either not necessarily glycation per se, but methylation and some other modifications of genes that are in the male sperm.

44:33
And we found a really clear link between smoking and kind of overall health and well-being of sperm cells from dad. So we use that as some preliminary data. I would imagine because the same pathways are in play. Again, epigenetic control of gene targets by smoking may also occur in vaping scenarios. We just don't know enough to draw those conclusions yet, but stay tuned. We're hopeful that we'll be able to uncover some ideas there. Yeah, nice one. So Paul, if...

45:03
someone had to choose, like their currently smoking cigarettes, which to be fair, who can afford to smoke these days? I saw a 23-year-old smoke the other day and I'm like, where are you getting that money from? Like, are you rich? But if someone had to choose between smoking, I'm sorry, they're giving up smoking because they want to become pregnant, are they actually better off if they had to do anything and cold turkey wasn't an option, nicotine patch over a vape?

45:32
I would definitely go for the patch over the vape. The reason for that again is although the void that those folks are trying to meet is the nicotine withdrawal. You don't want to trade one addiction for another unless you can rule out all of the side players. If you had just the nicotine available, I have not smoked before and I would advocate just never doing it. I just know that I'm a realist. That's not always the easiest thing to say or do.

46:02
If I had to choose between the two and I needed that addiction met, yeah, you would go for the patch for sure above and beyond all those other side molecules that are generated, unfortunately, when that superheating occurs. Yeah, yeah. No, that sounds really sensible. Do the different flavors change health outcomes? And you've done a study looking at things, I mean, I don't know these flavors, red hot, green apple, and how they affect...

46:31
cal, sorry, cell carcinoma invasion. So what can you tell us about that, Paul? Yeah. So the flavoring is usually the most kind of dynamically controlled or user-based control when you look at all of these products. So we've been focused on obviously the effects of vaping secondarily. Our focus mostly before was, you know, in the areas of glycation and tobacco smoke. But with this new tangent, we're trying to address all the different tissues that encounter

47:01
these types of flavors. Some of our research focuses on the first point of entry. That's in the oral cavity. What we did was we looked at two of the most common flavors at the time. This is a couple of years ago. Red hot is a type of cinnamaldehyde type of flavoring. People, based on personal preferences, have enjoyed that over the years. Then green apple is more of a sweet, tangy, fruity type flavor. Really a combination of several tastes, not just apple, but that's the trade name.

47:31
So, what we found is that those two flavorings, the two most kind of popular ones at the time, had diverse responses that follows in the tissues. We found, for instance, red hot flavoring increased cell invasion, so it made cancer cells more cancer-like. And that was observed in gingival cancer cells. But green apple flavor decreased that. So, again...

47:56
The other side of the coin doesn't necessarily say, hey, if you have oral cancer, please make sure you select the green apple flavoring because you're again hitting them with so many other things that you just don't want to make sense of that. But what that opened our eyes to is whether it was with or without nicotine, there are definite responses to these flavors. In a cancer setting, they're modulating rage expression. So they're making sure the receptor is in place to bind the flavoring metabolites.

48:26
molecules that cause inflammation. Those are called cytokines and chemokines. In those projects, we also looked at various MMPs. That might be the first time for some. MMPs are matrix metalloproteases. So what they are, they're proteases, they're protein enzymes, and what their job is, is to chew through matrix. So the more often you have these MMPs, the more likely your cancer would be invasive. And we want to stop that.

48:55
We don't want metastatic cancer. We want it to stay where it is if you have to have it at all. But we found that these chemicals also modulated MMP expression, further enhancing the invasiveness of these cancers. Now that's in the oral cavity and we're currently fleshing out those same types of results or the same types of biomarkers and lots of other tissues in response to exposure. Remember, ultrafine particles get in.

49:22
burst off in the oral cavity, but they make their way through the lung, bypassing all of our defense mechanisms there like cilia and mucus, and they penetrate and enter into the bloodstream. So what do they do when they take up residence in muscle tissue or fat tissue or the gut, right? That's quite a bit removed from the lung, one might say, but intimately connected nevertheless.

49:51
oxidative stress metabolites created. If someone has an autoimmune condition or an already inflammatory condition, if they are choosing to vape, then that's going to make, their health outcomes will be far worse, I imagine, than someone who might have quite a relatively free of that. Yeah, no, absolutely. Again, the name of the game while surviving on this planet is to...

50:20
turn on inflammation to fight off the bad guys that we run into, cuts and bruises and things like that, but then turn it off or at least turn it down enough to where it's not a long-term problem. So if you already have an autoimmune issue where some of that's kind of lurking in the background, adding more inflammation, both pulmonary and systemic is a recipe for disaster. You know, unfortunately, a lot of these inflammatory processes don't burn out. I'm thinking of, you know, COPD for instance.

50:48
problems with COPD is the exacerbation. You know, patients present to the clinic not looking for, hey, can you cure my COPD? No one knows how to do that. It's more so, can you help me survive the day because this inflammation is so debilitating. They just don't burn out. They feed on themselves. Yeah. Oh, I know. Paul, if someone was just like, look, mate, I'm going to vape. What can I do to help potentially reduce my risk?

51:17
in and around it? Are there any potential therapeutic things that they can do? You mentioned carbohydrate restriction as just earlier on in our conversation. I wonder whether you feel that's relevant here. What else? Yeah. So, I think that's going to help quite a bit is to mitigate. Again, the goal is no matter what you're exposing yourself to, can you minimize or mitigate the responses to whatever that is? So, there's smoking, there's vaping.

51:45
particulates in the atmosphere, whether they're vehicular exhaust particles or fine dust. You know, you're in the sub-Sahara desert on a bad windy day. All of these that are PM2.5 and what that means is particulate matter that's small enough to where it penetrates the pulmonary, we need to mitigate that. So, are you going to survive on this planet in the complete absence of all of those? Not likely. But the more we can...

52:11
reduce the fuel that you're feeding onto these receptors the better. One of the main things you can do to mitigate the glycation rage pro-inflammatory axis, which is one of the big drivers in smoking and vaping. And again, for clarity, just to be sure, that is not the only thing that will perpetuate inflammation. I don't want folks to think, let's just make a drug and cut out rage and then everything will be fine. There are parallel pathways that are there as well.

52:41
let's just stop throwing fuel on the fire. If we control our carbohydrates, that extra sugar, again, beyond burning it, storing it, but that that's used for glycation can be minimized. And that would slow down the activation of the receptor and make you do a little bit better. Yeah, nice. And what about artificial flavors in foods, actually? Like, did they...

53:05
go down a similar inflammatory pathway in certain examples? So if someone cuts out carbs but is still eating a highly, I don't know, I don't know what they'd be eating, but a lot of these sort of flavored foods, would that still add to risk? There definitely are some clear parallels between the effects of vaping flavors, if you're thinking of the flavor in the module, and comparing those, if you will, to the artificial flavoring and processed foods.

53:35
The problem in addition to the actual flavoring causing problems from a vaping standpoint is that the vape flavoring also because of the superheating becomes those carcinogenic bad guys too. So there is a metabolic health and inflammation link, both trigger the similar biological pathways despite, you know, I think targeting different systems. But you know, I think the main thing we want to avoid is the e-cigarette flavorings, particularly those that make aldehyde containing compounds.

54:05
Those are the ones that are going to promote oxidative stress, pro-inflammatory cytokines and cancer invasion more so than some of those that are not modified. You know, there's just such a great link there that we need to know more, particularly because they both of them can, you know, penetrate the bloodstream, can access points in the body that we don't intend. Yeah, for sure. And you know, I think about some of the pushback, I'm not sure if you get any pushback on...

54:32
research into vaping from people who are strong advocates because of the potential to reduce harm because people aren't smoking. I feel like someone might say, come on, Paul, maybe a lot of that research that's been done looking at poor health outcomes are on former smokers and the damage has already been done. But you do mechanistic trials as much as anything.

54:57
We do and that's why our grant focuses on the cellular aspects. We really want to tease out the mechanisms and the genes involved and then extrapolate those same mechanisms in mouse models. And what that does is help to inform better human studies where you can recruit folks that have, you know, specific genetic backgrounds, whether they be racial backgrounds or demographical type backgrounds or actual gene manipulations. So...

55:23
Yeah, that is the problem with any type of a pulmonary disease, speaking from the broader kind of perspective of where I'm coming from as a scientist. It's really hard to do studies that focus on COPD patients. And the reason for that is there are just so many comorbidities. If you have COPD, you are five times more likely to have diabetes.

55:46
vice versa. I don't have those numbers in front of me, but if you have diabetes, your tendency to develop a COPD phenotype is so much more enhanced. You have the inability to manage your blood sugar in one regard and that blood sugar therefore exacerbates the age rage axis in the lung. Rage is the fifth most abundant protein in the lung. So evolutionarily, there's a reason for that, right? Sure, we've got surfactants, we've got elastin and collagen that gives respectively...

56:16
distensibility and rigidity to the lung, but rage is right there with the top of them and why that's there is kind of a big conundrum. We definitely have all of these different research avenues that feed on one another and hopefully will shed some light on the overall picture. Yeah. Nice one, Paul. I really feel like you've enlightened, well, me, and I'm sure listeners will feel the same after this discussion because it's really great to talk to the people who are doing the research.

56:46
And also you translate it really well into language that we understand. So thank you so much for that. And I'm excited to see the outcomes of the next sort of the grant that you've just received as well over the next couple of years. Yeah, that'd be great. And love to stay in touch and keep you updated on how things go. Yeah. Amazing. Can you let people know where they can find you and your lab's work, Paul? Yeah. So we run a website, reynoldslab.byu.edu.

57:15
We have some updates there, but probably the best way to connect with me is on social media. I'm just starting in that area. So there's a place that folks can find me. All the main platforms. It's just Paul Reynolds PhD. So at Paul Reynolds PhD, Instagram, Facebook, X, those types of places. Amazing. Paul, thank you so much for your time this morning. Thank you. That was fun.

57:50
Okay, hopefully you enjoyed that. And honestly, if you know people who vape or who have questions about vaping, honestly just share this show with them because I just think it'll give people a little bit more insights into the entire health issue around it. And for people to understand that it isn't just blowing steam into your lungs. It is so much worse than that. Next week on the podcast, I speak to Dr. Gregg Peoples about the use of omega-3 fatty acids

58:19
athletic performance and health. Until then though you can catch me over on Instagram, threads and Twitter @mikkiwilliden, Facebook @mikkiwillidenNutrition or head to my website mikkiwilliden.com where you can book a one-on-one call with me. Alright Team you have the best week. See you later.