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Environmental Aggressors and Comprehensive Protection: Chelating Agents in Skincare

  • Authors: Diane S. Berson, MD; Giuseppe Valacchi, PhD
  • CME / ABIM MOC / CE Released: 11/30/2022
  • Valid for credit through: 11/30/2023
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  • Credits Available

    Physicians - maximum of 0.50 AMA PRA Category 1 Credit(s)™

    ABIM Diplomates - maximum of 0.50 ABIM MOC points

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Target Audience and Goal Statement

This activity is intended for plastic surgery and aesthetic medicine specialists, dermatologists, primary care physicians, nurses, nurse practitioners, and physician assistants.

The goal of this activity is for learners to be better able to make recommendations for comprehensive skincare protection.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Key components of skin protection to cover the entire spectrum of environmental aggressors
    • Role of transition metals in the skin
  • Have greater competence related to
    • Recommendation of skincare regimens to patients that encompass various mechanisms for protection


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  • Diane S. Berson, MD

    Associate Professor
    Private Practice Dermatologist
    Department of Dermatology, Weill Cornell Medicine
    New York, New York


    Diane S. Berson, MD, has no relevant financial relationships.


  • Giuseppe Valacchi, PhD

    David H. Murdock Distinguished Professor
    Professor of Regenerative Medicine
    University Faculty Scholar
    North Carolina State University
    Raleigh, North Carolina



    Giuseppe Valacchi, PhD, has the following relevant financial relationships:
    Consultant or advisor for: Nu Skin; SkinCeuticals
    Speaker or member of speakers bureau for: SkinCeuticals; Vichy
    Research funding from: SkinCeuticals


  • Briana Betz, PhD

    Medical Education Director, WebMD Global, LLC


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    Scientific Content Manager, Medscape, LLC 


    Renata Feldman, PharmD, has no relevant financial relationships.

Compliance Reviewer/Nurse Planner

  • Lisa Simani, APRN, MS, ACNP

    Associate Director, Accreditation and Compliance, Medscape, LLC


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Environmental Aggressors and Comprehensive Protection: Chelating Agents in Skincare

Authors: Diane S. Berson, MD; Giuseppe Valacchi, PhDFaculty and Disclosures

CME / ABIM MOC / CE Released: 11/30/2022

Valid for credit through: 11/30/2023


Activity Transcript

Diane S. Berson, MD: Hello, I'm Diane Berson, an associate professor in the Department of Dermatology at Weill Cornell Medicine in New York. Today we are going to discuss ''Environmental Aggressors and Comprehensive Protection Utilizing Antioxidants and Chelating Agents in Skincare.'' It is my pleasure to welcome Dr Giuseppe Valacchi, who will be joining me. Welcome, Giuseppe.

Giuseppe Valacchi, PhD: Thank you Diane for the introduction. I am a professor of regenerative medicine at North Carolina State University and also a professor of physiology at University of Ferrara, Italy. I'm very happy to share with you this topic today.

Dr Berson: Well, you've written some incredible articles on this topic with some great research, and I know this is very much of interest to us dermatologists who are seeing dermatologic issues of sun damage and environmental damage and inflammatory conditions on a daily basis.

We all know that skin protection is critical for maintenance of skin health. When we talk about skin protection, we're not just talking about protection from ultraviolet light, but also about the entire spectrum including infrared radiation, ozone pollution, exhausts, cigarette smoke, and even transition metals. So, when we talk about the sum of exposures to which an individual is exposed to over their lifetime, we refer to these as exposomes. Again, exposomes can include ultraviolet light, infrared light, cigarette smoke, ozone, pollution, exhaust, but also other factors such as nutrition, stress, even lack of sleep.

So, Dr Valacchi, when we talk about pollutants, again, we're thinking about ozone, particulate matter. What exactly are the chemicals that we are talking about?

Dr Valacchi: Yes, you introduce a very hot topic and a very large topic as well. So, the concept of exposomes, just to make it clear, is anything that can affect our life beside the genetic part, so anything that can be any spot. Part of that is also as you mentioned even the lack of sleep, and has been shown that even, and that is just a little parenthesis, even the change of our biological clock can actually influence skin health.

So going back to the pollution, it's clear that while the lack of sleep maybe you can do something in your life, pollution is complicated. We cannot really avoid it. When we talk about pollution, yes, in the dictionary we find just one word, but pollution is a complicated term because it includes several agents. But they are so different under the chemical and biological and physical point of view, that they have completely sometimes different wave of action. We will discuss this later, but the mechanism of action is crucial to how they will lead to a damage of the tissue, in our case, the tissues of the skin. Because as we all know, it is the first shield, the first barrier, again, the so-called outdoor stressors.

Dr Berson: Well, we know that ultraviolet light and pollutants do cause damage to the skin by creating oxidative damage and the production of free radicals, and along with that, the development of inflammation in the skin. Now as a result of this, we can see increased matrix metalloproteinases. We can see a loss of collagen. We can even see a compromise of our epidermal barrier. So, the result is that we are seeing premature aging of the skin which clinically can present as rough skin, wrinkled skin, discolored skin, even larger pores. But premature aging of the skin is certainly caused by both pollutants and ultraviolet light. But as a result of this inflammation, we might even see an exacerbation of the inflammatory conditions that we treat in dermatology such as eczema, psoriasis, or acne. Can you actually go into a little bit about the mechanism of action of inducing oxidative stress and inflammation involving metals?

Dr Valacchi: Yes, so thank you for this good question. That is a very important part of the pollution field, the mechanism. We know, in any pathology, if you are able to know the mechanism, you might be able to fight that mechanism and to at least quench part of the damage induced to the tissue.

In this case, we are talking about skin. The mechanism by which pollutants can affect the skin is completely different. Before going to the metals, I would like to underline how 2 of the main pollutants to which we are exposed daily are ozone and particulate matter. They have a completely different way of action. Ozone cannot penetrate the skin, but it reacts with a stratum corneum. It leads to peroxidation. Products that they will then affect the upper layer of the skin and induce cascade of biological product, but they will be the bad second messenger that will induce the noxious effect.

On the other hand, particulate matter is a very complicated topic. Particulate matter includes ultra-fine particulates and also much larger particulates. The idea that particulate matter can enter the skin is still under debate. But on the other hand, the fact that they enter or not enter the skin is a secondary, actually, problem because data, clear data have been shown by living in urban area where there is a high concentration of particulate matter leads clearly to increased dark spots in the skin, wrinkles, and also keratosis.

So, the fact that a particulate matter can be internally and has been suggested that one way of mechanism is to go through the skin using the follicle, hair follicle. The other is that maybe we don't absorb the whole particle, but what is attached to the particle. For example, aromatic compounds can be absorbed because they are lipid soluble, and they then will react and induce inflammation. The trick of the inflammatory process is the peroxidation. Peroxidation means that our lipids are oxidized. We need to think the oxidation of the lipids is not an end point but is a starting point.

Peroxidation is a second messenger. Several compounds that are part of the peroxidation cascade, for example, some aldehydes alpha beta and unsaturated beta aldehydes. I'll maybe show later and data on the 4-hydroxynonenal. They are second messengers. They're able to attach to proteins. They're able to change the confirmation of the protein, and they are able to even change the functionality of the protein.

This peroxidation is a consequence of an upstream mechanism. The upstream mechanism is usually driven by metals. The metals that are mainly involved in this process, when we are exposed to pollutants, are iron and copper. We know from our biological class that iron, the ferrous iron, the 2+ iron, can interact with hydrogen peroxide, which is a ROS molecule that is continuously made by our cell as a signaling molecule. That leads to ferric iron and hydroxyl radical. Hydroxyl radical is one of the most dangerous and most reactive, reactive oxygen species, that our body can encounter, because it's so reactive that immediately will react will lipids and induce this peroxidation process.

So, to wrap up this concept, if we are able somehow to quench or to stop or to minimize the effect of the metals on the tissue, we will prevent partially the peroxidation, and so we will not have the second messenger that then will carry on the noxious effect to be exposed to these pollutants.

Dr Berson: So, in actuality, ultraviolet radiation and pollution have an additive or synergistic effect on oxidation and inflammation. And these polyaromatic hydrocarbons from particulate matter and, for instance, cigarette smoke can actually absorb UVA and therefore be photo activated or exacerbate skin damage. It's fascinating.

I think that we all appreciate that skin conditions that we see, especially the inflammatory skin conditions in dermatology, can be associated with environmental pollutants. I know that as a dermatologist we all can appreciate that when we see our patients who've smoked cigarettes for many, many years, they certainly have changes in their skin. Their pores look larger. Their skin looks more rough and sallow, almost with a yellowness to it. They certainly have deep wrinkles. So there certainly seems to be an effect with cigarette smoking and premature aging of the skin. And I think that the environment, most probably also, influences other conditions such as atopic dermatitis, psoriasis, and acne.

Giuseppe, I know you've written some articles and done some research on this. Can you share some of what you have discovered regarding these conditions?

Dr Valacchi: Yes. So, what I’d like to underline here is also the fact that is when you talk about oxidative stress and you talk about inflammation, these are 2 phenomenons but are recalled as the chicken-egg puzzle. In this sense it is very complicated to understand who comes first and who comes second. But for sure, we know that they have a positive feedback to each other.

We actually describe this phenomenon as an ox-inflammatory process where both inflammation, oxidative stress play a role in these conditions, and has been shown by us and others that, for example, the exposure to pollutants such as ozone is correlated to increase of several skin conditions such as urticaria, dermatitis, rash, and even infections.

One thing that I like to underline is that what we need to take care of first in our skin is to maintain the skin barrier properties. Because if we lose that, our skin is more accessible, not only at that point to pollutants, but also to pathogen. That can further foment the inflammatory process and further bring to a more dangerous situation.

Some data that we just published recently, we showed that if we expose skin to a pollutant, a particle model, actually diesel exhaust engine was used in this study, we are able to clearly notice an increase of a peroxidation product. That confirmed that the mechanism is there. The ability of the pollutant to induce peroxidation is the driving force of the damage.

If we treat the skin with have a normal iron chelator, and so with an antioxidant mix, we were able to clearly show the difference in the data of peroxidation. In the sense, as you can see from this graph, you see that while you have in the gray bar an increase in peroxidation level in the untreated skin, you are able to almost quench completely these effect by using either an antioxidant mix or in combination with a chelant.

What does this mean? This means that you need to sustain your antioxidant properties of the skin with a chelant agent because this kind of has a parallel, but independent, effect. I show you more of the data that we have published in this paper. Beside the peroxidation, we need to understand what is the effect of that.

As I mentioned, alterating the skin barrier is a key process in damaging our tissue. Indeed, 1 protein that plays a key role in our stratum corneum and epidermis composition and barrier function is filaggrin. It's clear how here is the red staining, how the red staining is almost completely lost after the exposure to the diesel exhaust. You see in the untreated first figure. You'd almost don't see the red, but if you treat it either with a chelant and in combination even with an antioxidant mix, we are able to bring back the level of the filaggrin protein, which means that you are able to maintain healthy skin. And this was confirmed even with another protein, very important, again, for the health of our epidermis, that is involucrin. And also, in this case, you can see, especially after 4 days of exposure in the B panel, you can see how we lose the redness that, of course, the involucrin is more diffused in the epidermis. And you see that you lose the redness color, but when you treat it with this combination, you are bringing back the dye fluorescence. What does it mean?

Means that also in this case we are able to prevent the modification of the skin barrier, and so our skin is more protective against the pollutants. But does this have also consequences? Diane earlier mentioned about MMPs and collagen. We know how these are 2 elements that are, let's say, a trademark of skin aging and skin damage. In this, I can confirm, but when you are exposed to the diesel exhaust, again, you have a clear increase, as you can see here in these images, a clear increase of MMP-9 that we know this is active MMP-9, means it chooses our collagen. It chooses our matrix and lead not only to an inflammatory process, but also to wrinkles, as we know. That's why we always want to maintain the level MMP-9 low because, at the physiological level, otherwise we lose this matrix where our actually skin holds on.

Also, in this case, treating the skin with a chelant or with an antioxidant mix, especially when there is a combination, we are able to alleviate and to almost quench the activation of MMP-9 in the skin. That leads, as this is the last figure that I wanted to share with you, to a loss of collagen, as you can see. Especially after 4 days in the panel B, you see that untreated diesel-exposed skin almost loses the green dye that is a marker for collagen one. And again, we are able to replenish this effect thanks to the use of a chelant and an antioxidant mix.

Let's say that the summary of the study is that we need to protect our skin not only with an antioxidant strategy but having also in a compound that can alleviate the effect of metals, can really have an additive and much more protective effect of our skin when exposed to outdoor stressors.

Dr Berson: Giuseppe, your work is really fascinating. Just it's so wonderful to see that you actually studied lipid peroxidation and actually looked at filaggrin and involucrin, which we know is affected certainly in our atopic dermatitis or eczema patients. And then that you looked at MMP and collagen, which we know plays a role in photoaging and chronic photoaging of the skin and therefore the signs of premature aging of the skin. But it's fascinating to see that you studied the effects of ozone and pollutants really creating the same phenomena that we see with chronic photoaging from ultraviolet light.

So, Giuseppe, can you tell me, are there metal chelators also in some of the botanical products that we use for skincare?

Dr Valacchi: Oh, yes. There are several that have been proposed and used. As we know there is for sure kojic acid. But some chelators that has been now added to many formulations are for sure the kojic acid and chlorogenic acid. That have been shown to prevent the formation of hydroxyl radical, the bad guy that I mentioned earlier when we explain the Fenton reaction.

So, chelating this compound, we are able to prevent the peroxidation. But on the other hand, many of these polyphenol or flavonoids or natural compounds, how they actually defend our skin is also via the activation of endogenous system, antioxidant system that is called Nrf2. That, actually,  once activated is able to transcribe for all the enzyme machinery involved in preventing the formation, or in the degradation of several reactive oxygen species. Among them there is for sure the catalysts, glutathione peroxidase, the superoxide dismutase. All these are transcribed by the same transcription factor that is activated by the natural compounds. So, from one side, you have of course all the low molecular weight antioxidants mentioned earlier that protect us topically, immediately from reaction. On the other hand, you have instead more less transient activation of our enzymatic antioxidant activity.

Dr Berson: So, this is great. So, we not only get protection from our antioxidants, but actually also some of these botanical products that also contain metal chelators.

Dr Valacchi: Yes, exactly.

I would like to underline here that 1 of the main effects that UV light has on skin is actually to increase the release of free iron on a skin. So, using some chelation when you are exposed to sun is very important because UV can even exacerbate the pollutants-induce iron effect, because from one side, UV releases iron from endogenous, from the cells, because the damage. From the other, you have pollutants such as particulate matter that brings more iron to the tissue. So, chelation is for sure a way to go to protect our skin.

Dr Berson: We know that kojic acid is also helpful for hyperpigmentation, and certainly that the polyphenolic flavonoids such as soy and green tea are actually very potent antioxidants and anti-inflammatories.

But I think that the main ingredients we all think about when we try to combat this damage are the topical antioxidants. Now certainly we have our own endogenous defensive mechanisms. And when we talk about the exposomes, the internal exposomes are important too. And we do see oxidative damage internally, whether it's in our lungs or our heart as a result of our normal oxidative activities within our bodies.

But when it comes to exogenous damage, there are certainly a lot of topical ingredients that we can add to our products, and these are essentially antioxidants. Antioxidants remember, have anti-inflammatory properties also. So, they're going to help combat the reactive oxygen species or the oxidative damage that occurs and the subsequent inflammation that occurs.

Some of the ingredients that I recommend patients use include the antioxidants vitamin E, vitamin C, vitamin A, which is retinol, and niacinamide or vitamin B, which also helps restore the barrier along with coenzyme Q and caffeine. But there are now also chelating agents, and these chelating agents combine and essentially bind with the metal ions and prevent them from chemically reacting with other substances.

So certainly, if I want to apply this to my own clinical practice when I'm treating patients, whether it's for acne, rosacea, whether they have seborrheic dermatitis or eczema, or certainly those interested in anti-aging and decreasing the premature aging of their skin, the ingredients that I do recommend are an antioxidant usually layered under their sun protection, under their sunblock. And I usually have them use the antioxidant in combination with a chelator and, again, the sunscreen on top. This is a way for our patients to protect their skin.

And therefore, I usually do recommend the antioxidant in the morning. There are different formulations, but I actually like the serums because if a patient can apply an antioxidant serum and then it applies very nicely and cosmetically under makeup, moisturizer and, of course, their sun protection, and it just glides on nicely under the sunblock. So, I usually have them use their antioxidant in the morning with their sunblock. Then of course, I have them use their retinol at night, which might help repair some of the damage.

Do you have any comments about what ingredients you like to use and how you like to recommend them?

Dr Valacchi: It was very nice what you said in a nice summary. What I would like to underline is also that these antioxidants, vitamin C, vitamin E, and also thiols, they are all connected to each other. So that's why I like to use the word antioxidant mix of more than one. Because for example, as we know, vitamin E has been sacrificed and protect us from our oxidants. It's able to be recycled by vitamin C and to recycle vitamin C, you need the thiols. So, this is why I say that. I say that because it's very important to have a mix antioxidant, rather than just one.

The second part that I would like to underline that is very good to mention is that many compounds, such as polyphenols, are able to defend our skin not too much by antioxidant properties, but because they're able to treat our endogenous antioxidant defense through some signal transduction pathway that will make the skin and cells more prone to fight oxidants.

Dr Berson: Great. Well, this has been a great discussion and I think that we can conclude that there are many environmental stressors, including ultraviolet light radiation, but also cigarette smoke, particulate matter, exhaust. And these all can impact the health of our skin. We know that inflammation caused by environmental stressors certainly can lead to further inflammation, further reactive oxygen species and oxidative damage in the skin. So, in addition to daily sunscreen, inclusion of antioxidants and metal chelators into our routine skincare can certainly be beneficial to decreasing premature aging of the skin. Giuseppe, I'd like to thank you so much for this great discussion.

Dr Valacchi: Thank you so much, and it was fun to talk about this topic. I hope that it's clear enough and it piques even more curiosity and more research and science on this topic.

Dr Berson: Thank you.  I'd like to thank you all for participating in this activity, and please continue on to answer the questions that follow and complete the evaluation.

This transcript has not been copyedited.

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