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Dr. Maria Zhivagui, is a postdoctoral researcher at the University of California, San Diego. She earned her PhD degree in Environmental Toxicology and Cancer Genomics at the World Health Organization (WHO)/ International Agency for Research on Cancer (IARC) in Lyon, France. Her research focuses on cancer prevention and the identification of cancer-risk factors to reduce cancer incidence and provide humans a better environment to live in.

Could you tell us a little bit about your background and what led you to your current area of study?

I started off my PhD at the World Health Organisation, specifically working with the International Agency for Research on Cancer known as IARC.

Their mission is to prevent cancer, and identify the causes of cancer in order to prevent them. When I started my PhD in 2014, my studies revolved around identifying the mechanism of action of certain cancer risk factors. The aim was to identify the compounds or exposures in our daily lives/ environment that can lead to cancer. To tackle that question, we addressed the molecular mechanisms by looking at DNA mutations. By matching the patterns that we observed upon exposure to cancerous factors, we could identify cancer samples/ human biopsies that might have been caused by a certain cancer.

Later on, I was recruited by Dr. Ludmil Alexandrov to start my postdoc at UCSD. Both of us were still interested in identifying cancer causes in the environment, in particular, addressing some public health concerns. Then, when I came to the US, there was a lot of hype about certain cosmetic procedures, especially those involving artificial UV lamps. We were both interested in this field, and after reading so many medical reports from dermatologists suggesting a potential link between cancer and artificial UV lamps, we wanted to dig deeper and study it experimentally.

It certainly is a very interesting area of research. Can you tell us a little bit more about the current understanding of exactly how ultraviolet light relates to cancer, in particular, which cancers it's linked to, the genetic damage it causes and the effects of different wavelengths of UV light?

UV radiation is split into three different subclasses. First is UVC, which is the lowest wavelength UV radiation and is termed ‘UV germicidal’ because it is mostly used to kill germs and parasites, making it very important and typically used in labs. Its low wavelength makes it very potent, letting it hit really deep in the tissues, cross glass and a lot of other barriers too.

The next class is UVB, this ranges between 280 to 350 nanometers. Around 10% of the UV light that reaches Earth from our sun is UVB radiation, and it's responsible for a plethora of DNA damages. For example, it can hit deep into your DNA and lead to dimers that can lead to mutations later on. It's also responsible for skin cancers, particularly melanomas, which are very dangerous.

The last class is UVA radiation, usually classified between 350 to 400 nanometers, 90% of the UV light that reaches Earth from our sun is UVA radiation. UVA is known to be linked to skin cancer development in humans as well as the tanning effect. UVA, in terms of mechanism and genetic changes, is known also to cause some changes in the cell, for example, it can lead to DNA breaks, often indirectly, because it doesn’t hit DNA as strongly as UVB, but it can still hit the deeper layer of your skin. It can actually penetrate deeper than UVB due to its larger wavelength. Besides DNA breaks, it can also lead to reactive oxygen species production. Reactive oxygen species are very tiny molecules that have a huge amount of energy and are very reactive in the cells. They bombard many cell components such as DNA, RNA, lipids, mitochondria, proteins, etc, so they are very dangerous, and they can be produced by any irradiation type.

How does the UV emitted by the nail dryers that you were researching compare to the radiation from other places humans might be exposed to UV light? So for example, sunbeds or even natural sunlight.

All of them have UVA radiation, that is the main component. We do know though, that some UV lamps used in nail salons (and tanning beds) also emit UVB. These are on the higher spectrum of hazard or danger to health. They can have more negative impact on human health when they include UVB, but the machine that I used emits mainly UVA radiation.

How does the UV radiation used in a lab, for example during some types of gel electrophoresis,fit into this spectrum? Has there ever been studies on this?

UV usually used in labs is UVC radiation, which is the most dangerous one. It's really scary because when we are working on cell culture, we very often use it every hour. We turn it on, and if somebody is passing through the lab in between each experiment, you are somewhat exposed to the UVC. Luckily we do have hoods which have glass that protects from the UV radiation emitted from inside. We always take preventive measures for these applications, but these UV radiations are found not only in labs, but also in other industries for example, water treatment, in cosmetics etc. We try as much as possible to prevent and limit our exposure by taking preventive measures such as wearing PPE, protective gloves, lab coat, even a mask. However, when you go outside the lab and outside work, you unfortunately see the use of these UV lamps in cosmetics and daily life. People are in this case, often not aware of the dangers and don't use protection. It is quite funny to think that we take it so seriously in the lab, but when you go outside, people tend to just use it normally. I was actually a user of these UV lamps in nail salons for gel manicures, but no research was out there to tell us what's going on, so how were people to know how dangerous it is?

Can you talk us through the study design? And what was your initial hypothesis? And how did you go about testing it?

The hypothesis was to investigate the molecular and cellular changes (such as DNA damages and downstream mutation induction) from UV radiation. The lamp we used had been marketed as ‘safe’, but we did not find any regulations/ studies to measure that ‘safety’. To look into this, I devised a study design working with three different cell lines. All of them were primary cells (meaning they had not been exposed to something else) allowing us to start from the baseline and then look at any changes caused. There were mouse embryonic fibroblasts, which are well known and widely used in this field for detecting mutations. It's a very universal cell model that I’d also used during my PhD. Next was a human dermal fibroblast, originating from a male, and third were human epidermal keratinocytes (actual skin cells from an adult female). I wanted to expose the cells to different doses/ irradiance of UV light, so I purchased a UV machine from Amazon (anybody can actually purchase this exact machine for use at home or in a salon!) and exposed the cells for a range of times. Specifically cells were exposed from two minutes up to 20 minutes. First, we looked at cell toxicity and then for the downstream effects, we wanted to look at mutations. For this, we mainly focused on the 20 minute exposure, which reflects a typical UV gel manicure session. Finally, to study the mutations, we sequenced the DNA using state of the art technologies by performing whole genome sequencing or single molecule sequencing (for cells that couldn’t really grow fast and culture).

We've talked a little bit about the study design, but when it came to analysing the results, what role did COSMIC or any of the COSMIC products play?

The COSMIC database, in particular the mutational signatures, played a huge role in the research. I was able to match the mutation profile that I got from my experimental models and identify a known signature or mutational signature that is typically found in human cancers. Denoted as SBS 18, is it responsible for reactive oxygen species, so this allowed me to understand what's going on at the deeper level in my cells. When I looked at the aetiology of the signature, it was suggested that it can be linked to reactive oxygen species formation or production, or what we call oxidative damage/ stress. This helped us to not only better understand what's going on at the molecular level, but also to validate our preliminary results. For example, at the beginning, we did a number of experiments to address DNA damage and molecular effects, and for that I measured reactive oxygen species production immediately after exposure. I looked at the mitochondrial function and damages, and these showed me that right after irradiance with this UV curing device, we observed an increased level of oxidative damage, mitochondrial dysfunction and mitochondrial damage.

We then looked deeper at the downstream effects of all these damages, and observed mutations that reflect these preliminary damages caused immediately after exposure. So what does this tell us? It tells us that when you are exposed to these UV rays from these UV curing devices, we observe reactive oxygen species production that are not being repaired by the cell because the cells are getting too exhausted from the amount of damages caused by these UV rays. In our downstream analysis, we saw that this led to mutations that were engraved on the genome of mammalian cells.

Will this data be added into the mutational signatures dataset on COSMIC?

Interestingly, I am responsible for building a compendium/ catalogue for experimental mutational signatures that will go into COSMIC. Here I will be mentioning my data, but I'm not sure we will be adding it to core COSMIC. I think this is one of the ultimate goals though, to link COSMIC signatures to the experimental signatures I’m working on. So it is possible that in the future, we will have this aetiology included as a signature, which would be cool, and makes sense considering the strong evidence that we have published.

Is there anything specific you'd like to cover from your study that you think the audience would be really interested to hear?

What we found is: if a client goes for a gel nail manicure (which typically requires the usage of UV curing device), they’re under the UV for a total of 10-20 minutes. The UV rays hit the deep layers of your cells because UVA, as I said, are long wavelengths so penetrate into the deeper layers of your skin. When the cell is hit, it will absorb some of this UV radiation that will then attack your mitochondria, which is responsible for all mechanisms and metabolism, including respiration. When these UV rays hit your mitochondria, it causes mitochondrial fission, meaning the membrane of the mitochondria is no longer functional, they are dissociated and no longer work as normal. Further to this, we saw that the mitochondria produced a lot of reactive oxygen species, that then go and bombard everything in your cells including the nucleus. Damage to the nucleus means damage to the DNA.

You can see this knock on effect, first the skin, then the mitochondria, then the reactive oxygen species, the nucleus and finally the DNA.

Once we had seen this damage, we waited for the cells to culture and found that even after a long time, these damages are not being repaired. Rather, they were translated into mutations on your DNA that can lead to negative downstream effects. Some of these mutations can be passenger mutations, some drivers and it’s these driver mutations that are really concerning, especially when they hit an important gene i.e a driver gene. This is a gene that is typically responsible for cancer development and oncogenesis, if one of these is effected, it will be transformed to a cancer cell that will grow unexpectedly without limit on its lifespan. This is what's happening in terms of downstream effects and deleterious effects from these UV Nail drying machines.

You talked about including both human mouse cells in this piece of research, were there any notable differences in how these different species reacted to the light?

Interestingly, we observed the same effects on all of the cell models used whether mouse or human cells. We observed, in terms of quality, the same induction of reactive oxygen species or oxidative damage, the same increase in mutation counts, and the same effects on the mitochondrial function.

How worried should people who've been using these devices for years be? What advice would you give to them?

Now there is a thorough study that has been done experimentally on these UV rays, we can make people aware of what is going on at a cellular level. This can allow the user to weigh up the risk in terms of exposure, and I would definitely recommend these users to limit their exposure to UV machines now we know what they are doing. Limiting exposure is the best way to mitigate damages and downstream negative effects on human health. I would recommend to consider preventative measures, for example, using protective gloves and simply applying sunscreen! Just as we do when we go out of the house into the sun, we often use sunscreen to protect us from these UV rays. We have to do the same thing when we go to a nail salon, given that the radiation emitted from these machines is the same as we get from our sun.

Where do you see this going in the future? This is definitely a first of its kind study, are there plans for possibly more epidemiological type studies to explore this more human and less cellular level?

We will definitely need epidemiological studies to be devised to address the cancer induction from these UV machines and quantify the increased risk to skin cancer in human subjects. Hopefully, some of these are being devised right now. However, the thing with epidemiological studies is that they take around 10 to 20 years, and by then it may be too late for some of the users to stop or to be aware of the effects of these UV rays. At this moment, we know these UV rays are damaging to the DNA and to the cell, to know if it can cause risk, this will take some time. However, I think that users, even estheticians, should weigh the risk and know that these UV rays might lead to other deleterious effects on human health, probably cancer. Something else we may know in the coming decades is whether it leads to ageing or other deleterious effects.

I have to stress that there are some people who are hypersensitive to light, and they should be cautious about going into such a process or procedure. Some people that are, for example, under treatments like antibiotics have light sensitivity, and that would make them at a higher risk than others to these UV rays. Other susceptible people are older people, fair skinned people, and redheads; this is a huge part of the population who need to weigh the risk. These people need to be wary of the effects and downstream negative impact while waiting for epidemiological studies to ensure they don’t find out too late. Me? I immediately stopped using the machines. The result I had in my paper was enough for me to understand I need to limit the exposure and probably consider alternative procedures or services for my manicures.

How long do you think it’ll be between exposure and seeing it in the population?

I would not know myself because this will need a quantification and this is why we need epidemiological studies. Hopefully, we can have several epidemiological studies giving us hints and contributing to a bigger study where we actually quantify and witness cancer induction and development. What I can say is: it would depend on the regularity of usage, and the machine used. Each one is different, some have just UVA, some UVA and UVB, some have varying numbers of lamps etc and we know regular exposure leads to a higher risk of cancer.

In the US they found beauty pageant contestants were developing rare cancers on their nail, finger and dorsum of the hand, and the dermatologist attributed it to the recurrent exposure to these UV rays. These contestants were using the curing devices more regularly than the average person, and the cancer induction was faster. We will hopefully see epidemiological studies on more average users, I expect in that case we will see it takes longer for the cancer to develop. A study like that would really help us quantify the odds of getting cancer and the time it takes to develop.

I'd love to know if you're exploring any other environmental exposures and their relation to cancer currently, is there anything else you're working on that you can share?

I also worked on burnt food and their relation to cancer. We found that it's linked to kidney, liver and lung cancer. That was a very interesting study too!

Particularly with this piece of work, you've had so much media coverage. How have you found this, and how important do you think science communication and media presence is around subjects like this for scientists?

It's very important to have the media and the science community more linked and bound, to enable the public to understand what's going on, what are the updates? What did we find? A lot of findings go unknown and remain hidden, even if you have a big finding, if the media didn't probably cover it properly, people still will not be aware.

I'm glad that this paper got all this media attention because it addressed a public health concern concerning many worldwide. I've read a lot of reports online, from people questioning, is this bad for my health? Is it safe? Where is the data on this? The fact that we can now make people aware and knowledgeable about the effects of these devices makes me very happy. I always hope for a better environment, this is my passion. I would like us to live in a better environment and a healthy environment, where we can live longer as humans and in good health. This is what led me to this research: I want to know exactly what is in our environment that can have a negative impact on our health and hopefully give an insight into the preventive measures we can take to limit our exposure. We can live in a better environment and a better world that allows us to live longer and healthier. As scientists, we need the media, we rely on the media to reach the public, to make them weary of some things and to help them understand what's going to be the impact of their habits, whether in their diet or in the environment.

(Photos from UC San Diego Jacobs School of Engineering)