Episode 77: Glyphosate’s Long-Lasting Effects on Brain Health

Episode 77: Glyphosate’s Long-Lasting Effects on Brain Health

Karie Dozer [00:00:04] I'm Karie Dozer and this is TGen talks. You've probably heard a lot about the chemicals used in Roundup and other common herbicides used by farmers in the United States in growing and processing their crops. A new study by researchers at TGen and Arizona State University is shedding light on the effects of glyphosate, a chemical used in many herbicides on the brain. In this episode, you'll hear from one researcher whose work aims to identify the link between glyphosate and neuroinflammation. His study explores the idea that glyphosate can damage the brain long after exposure and can accelerate the progression of Alzheimer's disease. Our guest on this edition of TGen Talks is Dr. Patrick Pirrotte. Alzheimer's Researcher, Intense Early Detection and Prevention Division. Dr. Pirrotte, thanks for taking the time today.

Patrick Pirrotte, Ph.D. [00:00:55] Thank you. It's a pleasure to be here.

Karie Dozer [00:00:57] Tell me what you do here at TGen. What's your day to day consist of?

Patrick Pirrotte, Ph.D. [00:01:00] Yeah, I'm an associate professor in the newly minted Early Detection and Prevention division. I have been a t gen for probably about 13 years. And my studies, I mean, I've focused mostly on ovarian cancer, although I've been obviously working quite a bit on glyphosate exposure over the last couple of years. I also run our mass spectrometry facility both at Tiguan as well as at City of Hope.

Karie Dozer [00:01:27] What is glyphosate?

Patrick Pirrotte, Ph.D. [00:01:29] But I have was it is a herbicide. It's a weed killer that has been around since the 70s. It's ubiquitously used in agriculture. Probably about 300 million pounds of glyphosate are used every year in the United States. And this is just in the agriculture. On top of that, you have personal use, you have landscaping in city use as well. So probably about 400 million pounds that used annually. It's very effective. It works really well. Obviously, companies have developed what they call glyphosate, ready crops that are genetically engineered to be resistant to glyphosate. And it works really well, historically speaking.

Karie Dozer [00:02:16] What do we know about what glyphosate does inside the brain?

Patrick Pirrotte, Ph.D. [00:02:19] I mean, we didn't know anything about what glyphosate would be doing inside the brain at all. This is part of what we studied. What we knew was that glyphosate was specifically targeting a pathway. A molecular pathway called the sticky multi pathway, which is only found in plants. At least that's what we thought and was supposed to only kill plants. It was we all thought that it would not be affecting humans at all. Turns out that obviously now research has been done over the last couple of years in multiple different fields that are showing that glyphosate is involved in, for instance, preterm birth or sexual differentiation. We published a bunch of papers on that. We also looked at, for instance, associations with risk of developing breast cancer. And now our most recent studies have been focusing on its impact in inflammation and neurodegeneration and specifically Alzheimer's disease. We had a first study that was published two years ago that gained quite a bit of traction, that showed for the first time that glyphosate does indeed enter the brain. It crosses what we call the blood brain barrier. This was shown in mice. So this was a mouse study and that it was actually correlated with an increase in, in cytokines and specifically a inflammatory cytokines, a pro-inflammatory cytokines called TNF alpha. And that cytokine is very much a cytokine that is involved in in processes that are associated with Alzheimer's. And we actually showed this in a model, a mouse model of Alzheimer's disease as well.

Karie Dozer [00:04:05] A lot of us have heard the term blood brain barrier, but we're not exactly sure what we're hearing. What is it?

Patrick Pirrotte, Ph.D. [00:04:10] The blood brain barrier is essentially a gatekeeper for molecules that are supposed to not enter the brain. Many drugs actually known to not be able to cross the blood brain barrier, which is actually an impediment if you have a cancer developing drug strategy that actually can enter the brain is a topic in itself. And when you do studies like ours, you have to first show that a molecule of interest, such as here in this case glyphosate and its metabolite AmpA, because glyphosate is metabolized to AmpA, that those molecules can actually penetrate the brain and potentially accumulate in the brain.

Karie Dozer [00:04:52] How do you set about actually researching glyphosate to affect it in the brain if you're not actually studying humans that walk into your lab?

Patrick Pirrotte, Ph.D. [00:05:01] Yeah, that's a great question. There are many different Alzheimer's models that are currently being investigated. A typical model that is used a lot is what we call the triple transgenic model mouse model that basically harbors three different genetic mutations that are associated with Alzheimer's disease. And those mice actually develop cognitive declines that are similar to an Alzheimer's disease patient in this new study that we did. We actually exposed mice. We basically gave different doses of glyphosate to mice that were about five months old. And we those them for 13 weeks. And then we stopped and we then looked at their behavior six months later. And so one way of looking or assessing, for instance, cognitive decline is to use different tests such as the moist water maze, etc., which is, as you probably have seen it in movies, It's when a mouse is actually running around the little labyrinth. This is basically what we're testing. With increasing dose of glyphosate, six months after we stopped giving mice glyphosate, we saw that when mice were trying to go through this little labyrinth or maze, they were actually more anxious if they had been treated, and that anxiety actually increased with dose.

Karie Dozer [00:06:29] So the lack of exposure to glyphosate or when you take that glyphosate away, the effects don't necessarily go away. That's the simple takeaway.

Patrick Pirrotte, Ph.D. [00:06:37] Yes. For us, that was a major finding because most of previous research supposed that glyphosate and its metabolite AmpA were being cleared by the body, which means they are being shed or secreted mostly in urine. And when we actually dissected the brains of those mice after 12 months, so they had not seen any glyphosate for six months, we were able to detect, again, dose dependent accumulation of AMP, specifically the metabolite, the glyphosate metabolite.

Karie Dozer [00:07:13] Does that seem to indicate that the blood brain barrier is working in two ways? It's not only a gatekeeper keeping things out, but it might be keeping bad toxins in.

Patrick Pirrotte, Ph.D. [00:07:23] That's a great question. I think definitely it's permissive to most likely permissive to either glyphosate or AmpA. And what we suspect is, is that it increases specifically in some regions of the brain and those might actually be affected. When we later on looked at, for instance, also certain cytokine markers that we'd studied before. We again saw increased of those cytokines, the TNF, alpha, etc., those pro-inflammatory molecules. And we also saw, for instance, increased again with increased with those. We saw an increase in a number of different processes that are associated also with Alzheimer's disease or we call them amyloid genic processes, basically creation of beta amyloid and those usually involved in the development of plaques, plaques that are essentially lesions that accumulate or aggregations that accumulate in, in the Alzheimer's disease brain.

Karie Dozer [00:08:21] With your research, you're able to see the chemical changes inside brain tissue. How does it correlate and how can we hope to take those results and apply them to behaviors? If we have somebody in our family with a neurodegenerative illness. We're not as concerned with the label or the chemistry, but we're concerned with the behaviors.

Patrick Pirrotte, Ph.D. [00:08:42] First of all, the studies that we have performed so far are in mice. We need to be very careful to before we bridge actually to human studies. But clearly we need to continue studying glyphosate exposure in humans. We need to look for glyphosate in human brain. And we also need to continue associating behavioral studies with these glyphosate studies as well. I think these are the three critical aspects that we need to focus on.

Karie Dozer [00:09:17] How do you combine your research and how do you collaborate with other researchers to hopefully pool this knowledge to get the best answers and more quickly so that we can get to the bottom of Alzheimer's? And why it seems that so many Americans are diagnosed with it.

Patrick Pirrotte, Ph.D. [00:09:33] And we have about 7 million Americans that are diagnosed with or that actually have Alzheimer's disease. This s a large number of the population. We really need to use multi-pronged approaches. We are working closely with a colleague here at T John Matt Templeman, who is obviously steeped in behavioral studies, and he has his mind crowd study which looks at general behavior in the population in the aging brain. We also are very interested in working with the mobile lab that is actually driving around Arizona, collecting, for instance, MRI imaging with blood measures. And we would like to also include urine collections to be able to look at life. Was it exposure? I think we need to work with clinicians, so we're working with colleagues at Biennial Barrow Neurological Institute to really bring some of those human collection studies that are more controlled, because if you look at Mobile Lab and the participants that are enrolled into studies through the mobile lab, we're not really controlling what they eat, what they drink. But then if we look at the clinical setting where, for instance, we can actually get a more controlled population of patients that have been diagnosed with Alzheimer's disease, we can actually combine those studies together.

Karie Dozer [00:10:55] How was your research conducted for this particular paper?

Patrick Pirrotte, Ph.D. [00:10:59] This is actually an ongoing collaboration with a colleague at Arizona State University, Dr. Ramon Velazquez, who is actually Co-senior author on both our Alzheimer's disease papers, as well as Samantha Bartholomew, who's actually a first author on the paper as well, also at Arizona State University. And Dr. Ramona Velasquez has been a very productive collaborator in the Alzheimer's disease field in Arizona, and it's a pleasure to work with him.

Karie Dozer [00:11:28] And do you physically work in the lab with those two other individuals, or are you virtually working on the same project?

Patrick Pirrotte, Ph.D. [00:11:35] I think today it's probably a bit of both, right? We all of the mouse studies are conducted in Dr. Velasquez lab, while the molecular analyzes and specifically all the glyphosate analysis are conducted in my lab. This is only 15 miles away. So they just drop off their samples and vice versa. And that's how we collaborate.

Karie Dozer [00:11:55] What do we know collectively about glyphosate exposure and what might be an okay amount or safe amount? We tend to use that term and maybe what we have left to learn that might indicate that maybe we're retaining these chemical compounds throughout our life.

Patrick Pirrotte, Ph.D. [00:12:12] There is this term called Noel, which is basically means to the amount of life that is, it has no adverse effects and it's an upper limit threshold and that have been defined for most molecules. And for a long time it was accepted that glyphosate was essentially completely inert in the body and was not involved in any adverse effects. The research seems to be indicating that that's not true. I think the definitely dose thresholds are going to be have to be revisited. Which ones, what is and what is an appropriate threshold. That's something that is absolutely not known. And hopefully we will be able to get a better sense of that. We see obviously in the population, about 80% of the US population has traces of glyphosate in their urine. In my own studies, and I've probably profiled more than 1500 participants through multiple different studies, I would say that the vast majority, probably the number is higher. So it's probably those 80% are under estimated. I think we're closer to 95% or more. One of the major challenges when we were developing our assay was to find a proper controlled population that did not have glyphosate in urine. And it's still an ongoing challenge.

Karie Dozer [00:13:40] So bottom line, you've drawn out for most Americans that even if you don't work in agriculture, you're exposed to glyphosate at some point along the food chain because we're all eating.

Patrick Pirrotte, Ph.D. [00:13:51] Yeah, that is absolutely correct. And what I didn't mention yet is this glyphosate is also used not just to kill weeds selectively, but also as a desiccant. It actually dries out crops really well. Oats, for instance, or wheat in general are often, often have high levels of glyphosate. Similarly, glyphosate is also used to dry coffee beans, for instance. Many coffee beans had high levels of glyphosate. Some of it can be washed off, but sometimes those then penetrate into the into the membranes, the upper membranes or layers of food. And it's more difficult to remove that. Today we have a better understanding. I think in agriculture those processes are slowly being adjusted, but I think without a concerted effort, this is going to be an ongoing fight. Glyphosate has been was suspected to be a potential carcinogen. It's still on that list. W.H.O., or the World Health Organization has been flip flopping with the decision. Sometimes. See, they think it's a potential carcinogen. Sometimes they don't. I think a lot more research needs to be done to get to the bottom of that. We did some dyad studies. We found that some diets were more affected. If you are eating a green rich diet, if you're eating vegetarian, unfortunately vegetarian, but specifically non-organic foods, you may have more glyphosate, although the organic label in the US is also quite permissive and doesn't necessarily include the control of herbicides around the crops that are being harvested. I think it is extremely difficult to actually manage your glyphosate intake.

Karie Dozer [00:15:43] Might be impossible. What is next on your to do list? Obviously, there are a million ways you could take this research to advance it. Do you have an idea about where you will go next?

Patrick Pirrotte, Ph.D. [00:15:55] Definitely. One of the studies that we are very excited about is working with the mobile lab to start collecting samples all over Arizona, not just in urban communities, but also in rural communities, and try to understand whether glyphosate exposure is different in those different communities and then associate that with neurocognitive decline as well. That is a very important study that we're promoting right now. Beyond that, obviously, this is just one molecule, great graphics, glyphosate, its metabolite. We have interests in a number of other herbicides and also what we call forever chemicals such as P fast that we want to continue studying as well. Again, there's a lot that we don't know about those chemical compounds that we are using in everyday life.

Karie Dozer [00:16:47] Does research into glyphosate exposure and cognitive decline teach you and others in this field about Alzheimer's itself? Or is your focus purely limited to those compounds and the chemical effects they have inside our brain?

Patrick Pirrotte, Ph.D. [00:17:04] I think they teach us mostly actually about the Alzheimer's disease process because we are really finding those associations with increased plaque formation or increased production of beta amyloid or forceful tau, which is another hallmark of Alzheimer's disease. We also see those behavioral changes. So glyphosate exposure might not be causal, but it's certainly something that seems to be exacerbating the disease. And I think understanding how that submission occurs is something that we're very interested in understanding more.

Karie Dozer [00:17:41] What have I missed about this particular paper that you're releasing or about your research in general? What would you like people to know?

Patrick Pirrotte, Ph.D. [00:17:49] What attempting to be very thorough in our investigations. And so this is a mouse study. This is not a human study, although we are drawing some hypotheses that will be tested in human next. The reason why we work this way is because obviously mouse studies are much more malleable. We can we can study things that we cannot do in humans. We can't, first of all, dose humans with a certain concentration of glyphosate. It's also much more difficult to take a brain sample out of a human. We have to work with we will have to work with postmortem collections. And then it's often difficult to tie those postmortem collections back to how much play posit that that individual was exposed to during their life. I think most studies allow us to be much more controlled. But drawing those conclusions and actually mapping them to humans is what will be our next step.

Karie Dozer [00:18:52] Well, and for the millions of Americans who are living with someone with Alzheimer's, it probably gives them a little bit of hope. Dr. Barrow, thanks for taking the time.

Patrick Pirrotte, Ph.D. [00:18:59] Thank you very much.

Karie Dozer [00:19:02] For more on TGen’s research, go to TGen dot org slash news. The Translational Genomics Research Institute, part of City of Hope, is an Arizona based nonprofit medical research institution dedicated to conducting groundbreaking research with life changing results. You can find more of these podcasts at TGen dot org slash TGen Talks, Apple and Spotify and most podcast platforms. For TGen Talks, I’m Karie Dozer.