Exploring Environmental Health: Insights from the Yale Superfund Research Center on the Emerging Contaminant-Induced Cancers

November 13, 2023

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Yale Cancer Center Grand Rounds | November 10, 2023

Presented by: Dr. Vasilis Vasiliou

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00:00I'm Melinda Irwin.
00:01I'm a professor in the School of
00:04Public Health with Vasilis and also
00:06deputy Director for the Cancer Center,
00:09overseeing population sciences research,
00:12which focuses on lifestyle,
00:14genetic and environmental risk factors
00:17for cancer etiology and outcomes.
00:20So we're delighted today to have
00:23the Yale and National International
00:25expert in environmental carcinogens
00:28and cancer speak to us.
00:30Doctor Vasilis Vasilu,
00:31who is also he's the Susan Dwight
00:34Bliss Professor of Environmental
00:35Health Sciences as well as Chair of
00:38our Department of Environmental Health
00:40Sciences in the Yale School of Public Health.
00:43He received his PhD in Biochemical
00:46Pharmacology from the University
00:48of Ion Ionina in Greece.
00:51He then trained in gene
00:53environment interactions,
00:55molecular toxicology and pharmacogenetics
00:58at the Department of Environmental
01:00Health and the College of Medicine
01:03at University of Cincinnati.
01:04He joined Yale 10 almost 10 years
01:07ago in 2014 from the University
01:09of Colorado School of Pharmacy,
01:12where he rose to the ranks to
01:14become professor and director of the
01:16toxicology graduate program and was
01:18professor also of ophthalmology.
01:20He's established an internationally
01:23recognized research program that's been
01:26continuously funded by NIH since 1997,
01:28and his research interests include
01:31the etiology and molecular mechanisms
01:33of environmentally induced human
01:35disease such as liver disease,
01:37obesity and diabetes, cancer,
01:40and neurodegenerative diseases.
01:43Vasilis is the director of the N i.e.
01:46HS funded P 42,
01:48Yale Superfund Research Center
01:50and also the director of the NI
01:53AAA funded R24 Resource Center for
01:55Mouse Models and Metabolomics tools
01:58to investigate alcohol metabolism
02:01and tissue injury.
02:03This is really does translational
02:05research from preclinical work
02:07to clinical to community engaged
02:09research focusing on environmental
02:11risk factors in cancer.
02:13Thank you.
02:14Thank
02:16you very much, Melinda.
02:17Thank you for the invitation.
02:18And Melinda, thank you very much
02:20for the impressive introduction.
02:21I don't know if I
02:26anyway, so I wish.
02:32Let me start.
02:33Actually the talk of today's lecture
02:36is exploring environmental health,
02:39the insights through our P42
02:43Centre Research Centre on emerging
02:46contaminants and their their,
02:48their effects on cancer.
02:52So one of the concerns that we have is,
02:55you know that 50% or maybe more than
03:01more than 50% of the cancers might
03:04not be due to the genetic effects,
03:06might not be to mutations,
03:08might not be to polymorphisms
03:10or things like that.
03:11So they have an environmental impact.
03:13One of the things that has triggered
03:16my attention the last five or you know
03:206-7 years is the early onsets of cancer,
03:24which actually there was a very
03:27nice review in Natural Nature
03:30Reviews in clinical oncology,
03:33which posed the question if the early onset
03:36of cancer is an emerging global epidemic.
03:39And it has.
03:40As you can see, the incidence of of
03:43cancers in various organs in ages less
03:47than 50 and actually less than 40,
03:50has been rising in many parts
03:52of the world since the 80s.
03:54The evidence suggests an ideological risk
03:57of risk factor exposures in early life.
04:00Young, under hood,
04:01and all those specific individual
04:04exposures remain to be largely unknown.
04:06So this is what my interests are,
04:09how this environmental exposures
04:11could lead not only to cancers but
04:14also to early onsets of cancers.
04:16And we can go from liver cancer
04:19to colorectal cancer with
04:21associations to alcohol,
04:22which I could give you
04:24another lecture on that.
04:25But anyway,
04:25the early onset cancer epidemic
04:27might be 1 manifestation of
04:29increasing the trends of the in the
04:31development of many chronic disease
04:33in the young and future generation.
04:35So what we come here is the
04:39early life exposure,
04:40it's the exposures of the of the mother.
04:44And actually now it's also exposure
04:47preconceptionally for both mother
04:49and father what they have been
04:51into it and how this would affect
04:53the development of the embryon,
04:55the later studies.
04:56So the exposome includes
04:58environmental exposure,
04:59Melinda talked about diet,
05:01lifestyle,
05:01obesity and microbiome and this
05:04this exposome has changed completely
05:07in the last 40 or 50 years.
05:10So a lot of people looking into how this
05:13Eddy life exposures could have an effect.
05:16Of course we should not ignore the
05:18exposure we have on daily basis and
05:21talking about that one of the most
05:24important thing is drinking water.
05:26You drink your water and in most
05:28of the cases especially when you
05:30come to emerging contaminants,
05:32you don't you have no idea what
05:34what the water contains.
05:36So it's it's a lot of aspects in here.
05:39So talking about drinking water
05:42and protecting the environment.
05:44So the federal government has the
05:46Superfund Act and what that is refers
05:49to a comprehensive environmental response.
05:52Compensation and liability are
05:54known as CLEFCLA since the 80s.
05:56So what the federal government did
05:59is they put a law that provides a
06:02legal framework for clean up sites of
06:04contaminate and hazardous substances.
06:07Especially,
06:07you know there are some states,
06:09Connecticut is a heavily industrialized,
06:14actually it's a retired,
06:16it's a retired state of heavily
06:20industrialized area.
06:21If I'll show you the sites of superfunds,
06:26either federal or local,
06:28we might walk away and go and
06:29look for a job or another state.
06:31It's everywhere and I will
06:33explain you why in I'll
06:34give you some of these examples.
06:36Again, we have to be taking
06:39everything into consideration.
06:40So there is the federal law,
06:42if there is a company that has a spill out,
06:45so they're getting a fine and that could
06:47be hundreds of millions of dollars.
06:50So this amount of money,
06:52some of this amount of money they
06:53go to the EPA and some of them
06:56they go to National Institute of
06:57Environmental Health Sciences and what
06:59the environmental Health Sciences does
07:01takes this money and creates a centers.
07:04So you have we have here the Cancer
07:07Center at the same time we have
07:09the the Superfund research centers
07:11through around the the United States.
07:14And essentially the centers focus on
07:17the understanding of health effects of
07:19the exposures to hazardous substances,
07:21developing innovative technologies
07:24to mitigate essentially size,
07:27clean up and engaging communities
07:30affected by this environmental issues.
07:32So their research contributes to the
07:36overall goal of safeguarding the public
07:38health and environmental in areas
07:40of hazard or waste contamination.
07:42So this is what are the centers and
07:44this is as I said this is where the
07:47federal money from penalties from
07:49those cleanups go and they're coming.
07:51So how many centers that exist?
07:53We have 23 funded centers in the in
07:57the United States and as you can see
08:00on the top left is our Connecticut,
08:02it's a Yale Superfund Reset centre.
08:04This is the first ever centre we've
08:07got in Connecticut and the focus of as
08:11I said the focus of our the focus of
08:15our centre is on emerging contaminants.
08:18So what are water contaminants of
08:21emerging concern now these are chemicals
08:23that they're detected in trace amount
08:26in our drinking water within global
08:30drinking supplies that their risk on
08:34human health is not fully understand
08:37or even not been evaluated at all.
08:40OK.
08:41And what are these emerging
08:43concerns include that including
08:45industrial chemicals such as P Fas.
08:48Everybody has heard about the P Fas.
08:50Everybody you know today at least you
08:54will get educated on on 1.4 dioxane on
08:57some volatile solvents that they exist.
08:59But in addition to that we have
09:01a lot of pharmaceuticals,
09:03personal care products and actually
09:06yesterday NIHS had a webinar about the
09:09Expos on on personal care products.
09:12You'll be surprised how much they
09:14go down the drain and how much they
09:16end up in your drinking water.
09:17It's truly amazing.
09:19And of course you have pesticides
09:21and herbicides that come from
09:23the agriculture that eventually,
09:25you know they're going to end up into
09:28the water table and they're going
09:30to add up to our drinking water.
09:32So the overall objective of our Yale
09:36Superfund Research Center is to improve
09:39public health from the emerging water
09:41contaminants in the drinking waters.
09:44And what we're trying to do with
09:46trying to develop not innovative
09:48research in terms of the mechanisms
09:51of toxicities that they this
09:54emerging contaminants 'cause and
09:55also look at the ways that we can
09:59mitigate that we can detect and
10:01mitigate that and also
10:04inform the communities,
10:05talk with the communities, listen to
10:07their needs and talk to us about it.
10:10Our center has been focused on 1.4 dioxane.
10:14We and also it's what we call,
10:17I'm sorry walking around,
10:20I'm Greg, I'm sorry that's it's
10:23in my sense this is in my genes,
10:26it's not environmental.
10:28So it's 1.4 dioxin and what we call
10:32its Co contaminants which is 1,
10:35it's the dichloroethane,
10:37trichloroethane and also trichloroethylene.
10:40Those are volatile solvents that
10:42they exist and I will explain you
10:44why and how this has come up with.
10:46But essentially,
10:47this is what our center is doing
10:48and this is what we're focusing now.
10:50You can say why did you focus on that?
10:53So when I came here, it was 2014.
10:56I immediately went on,
10:59I think the next year immediately
11:01I met with the state authorities,
11:03the Department of Public Health
11:06and the Department of Energy
11:07and Environmental Protection.
11:08And I said I'd like to develop
11:11a Superfund research program
11:13for the state of Connecticut.
11:15What is the issue that you have?
11:18At that time?
11:19PFS were not that hot and
11:21actually thank God because we
11:23took the direction of 1.4 dioxin.
11:25Had they know anything about 1.4 dioxin?
11:27No.
11:28But they told me that this was the
11:30major issue and the major issue was
11:33because of this solvents on this
11:35multiple sites in the state of Connecticut.
11:37And the problem with 1.4 dioxin
11:40is they could not filter it.
11:43It would go through every aspect.
11:47And even in public water,
11:48they cannot filter it If if
11:50the source is contaminated,
11:52it will end up in your drinking water.
11:54So that was a major issue and This is
11:57why we chose to go with 1.4 dioxane.
12:00So the superfan center.
12:01And actually I'm really proud
12:03not because I got the grant,
12:05I'm really proud because I brought
12:07the four schools together and that
12:08is our school of public health,
12:10the School of Medicine,
12:11the engineering and the environment.
12:13And we developed this program.
12:14This program consists of,
12:16as you can see,
12:18four research projects and four course.
12:21We have the administrative core,
12:22we have the training core,
12:25the DMAC which plays the it's the
12:29data management and analytics.
12:31We also have the community engagement
12:33and of course we have the training,
12:36the training core that you're going.
12:37I'll go in a little bit more details
12:40when we move forward on this.
12:42So again,
12:4311 more time it was the concern
12:46of the public,
12:47of the public institutions was on
12:501.4 dioxin for a particular reason.
12:52Because it is a possible human carcinogen.
12:57It has been found that it causes
13:00cancer in animals,
13:02but now there is no epidemiological
13:05studies yet in humans.
13:07This is why it's emerging contaminants
13:10and it's found with the other Co
13:12contaminants and has been prioritized
13:15by US Environmental Protection
13:17Agency on the on the 3rd Unregulated
13:21Monitoring role for testing in
13:242013 and 2015 and you will see
13:26the map. It is spread
13:29throughout United States.
13:31So it's been also characterized
13:34as forever chemical just like the
13:37PFS because it cannot be filtered.
13:39It's very, it's difficult to be,
13:42you know metabolized by bacterial
13:45species and so on and it goes there.
13:49This is from the chemical Environmental
13:51news saying that this is really so when
13:54I put the team together, I put them,
13:57we wrote a big grant that we can
14:00we oversee what it was available,
14:02what was the scientific evidence,
14:04what was the demological studies,
14:07what are the strategies to mitigate that.
14:10And we we had that on a very
14:13nice review that actually helped
14:15us to get the team together.
14:18So 1.4 dioxane of course in three isomers,
14:211.41 point 2 and 1.3,
14:24but the concern and the most most
14:27prevalent is the 1.4 dioxane.
14:30Is it a new chemical?
14:31No, it's not.
14:32I'm just not going to go in
14:34all details of this because we
14:36can talk about for a long time,
14:38but it was first synthesized in 1863 and
14:42initially it was used as a stabilizer.
14:45It was used as a stabilizer for the
14:50for the solvents, the DCATCE and DCA,
14:55and what happens is this,
14:57this solvents, they were covered on.
15:02They were.
15:03They were transferred on aluminium
15:06containers and the aluminum containers,
15:08you know,
15:08they have a cover inside which
15:10is aluminum and they protect from
15:13being interacting with the metal.
15:16So what happened is after a certain
15:18period of time these solvents
15:20interact with the metal and they
15:23create even toxic products.
15:24So what they did is they found
15:27out 1.4 dioxane,
15:28it could block the catalysis
15:31of this reaction.
15:32So they were using 1.4 dioxane as
15:35a stabilizer of those chemicals not
15:37only to protect the toxicity but
15:40stabilize the solvents for their use.
15:43And what we're using this everything
15:45that you can imagine, I'll show you.
15:47So it was used as a stabilizer to begin with,
15:50but later as you can see from this,
15:52it has been used in many in many areas.
15:55So this is the uses,
15:57I'm not going to go in great details
15:59but includes from the stabilizing to medical,
16:02pharmaceutical, rubber and plastic industry,
16:06printing in and paints,
16:07adhesives, brake fluids,
16:09brake cleaning fluids and also rust
16:13remover and also antifreeze and deicing.
16:17The stuff that you they throwing on
16:20the airplanes before we take off on
16:22this it has 1.4 dioxide quite a bit
16:24and what we end up with on the ground.
16:28OK so pesticides and some of the
16:31pesticides they have up to 50% of
16:351.4 dioxide 50% anyway and also
16:39the consumer products we talked
16:41about before what is environmental
16:43concerns first of all ground water
16:46contamination resistance it's as I
16:48told you it's it's there it cannot be
16:51really degraded easily and can travel.
16:54It can travel everywhere toxicity.
16:56It's been classified,
16:57as I told you,
16:58as a possible human carcinogen by
17:01both the USEPA and the National
17:03engine for Recession.
17:04Cancer. Regulatory concerns
17:06are plenty of concerns.
17:08There is no federal regulation.
17:09Well, we don't have federal
17:10regulation yet, even for PFAS.
17:12And I don't know if you
17:15watch the movie Dark Waters,
17:17which I recommend that you do,
17:19you realize what what I'm talking about?
17:21About PFAS and regulatory issues.
17:24So as I told you before,
17:27what do you find, 1.4 Dioxane.
17:29You find all the other
17:31solvents or vice versa.
17:32It has happened in play many
17:34places in the United States
17:36around the Air Force or you know,
17:39army bases and everywhere.
17:40And it's not only in the United States,
17:43even in German Japan,
17:45China they have found whatever you find
17:49DC or DCA you will find 1.4 dioxin.
17:53So you expect to have it also in the rivers,
17:57in fish and in the drinking water.
18:00Here is the map from the you CMR 3
18:03and you can see there are white dots,
18:08I mean dots,
18:09Gray dots and red dots and
18:12essentially this is above,
18:14below and or around the
18:17recommendation concentration which
18:19is .36 micro grams per liter.
18:22This is a reference dose that
18:24this is the dose that it can
18:26cause one cancer per million.
18:28OK.
18:28And again this is advisory
18:31nothing regulatory.
18:32The areas we have chosen as it was here,
18:35you cannot believe if
18:37you live in Long Island,
18:39public water from Long Island
18:41comes from well water.
18:43And most of these areas,
18:44they're really high levels of 1.4 dioxide.
18:47And what happened on that?
18:48Actually Governor Cuomo was very
18:51strong and put the legislation and
18:54there is a law in New York now
18:57that prohibits the manufacturers
19:00to put 1.4 dioxane in detergents
19:03and household items.
19:05Now there is a lawsuit from the
19:07industry against the government,
19:08but you know,
19:08at least they put that and they
19:10recognize that because everything,
19:12and I don't have time to go through that,
19:15your tide, your your shampoo,
19:17your everything,
19:17it has 1.4 dioxane and everything is
19:20going to go down to the water table.
19:22And especially in Long Island,
19:25the public water comes from well water.
19:28So it's a major concern.
19:29Another area,
19:31which was one of the reasons that
19:35NIH had a very strong also thing
19:37is NIHS locates in North Carolina,
19:40major, major contamination.
19:41Also in North Carolina in the Cape
19:45Fear River is fully contaminated
19:47and you know it's still getting
19:49a lot of discharges in there.
19:52Is it only there?
19:53No, we have the case of Michigan,
19:55which I'll explain you later.
19:57We're working on that.
19:58Ann Arbor has a major plan of
20:011.4 dioxane sitting right there
20:02and there's a lot of concern.
20:05New Jersey found out last couple of
20:08years that the public water had 1.4 dioxane.
20:13And what happened there is a lawsuit.
20:14I haven't followed up the details,
20:16but in March 23 of 2023.
20:20The water companies shoot the
20:22manufacturers for putting 1.4
20:24dioxin into the river,
20:25which eventually ended up into
20:27the drinking water.
20:28So there's a lot of things going on and this
20:31is happening just right now.
20:33That was again in a different area in
20:35North Carolina where they found again
20:401.4 dioxin 1300 times higher
20:42compared to the reference level.
20:45So what I'm saying is there is a lot of
20:49issues in there simply because was not
20:52nobody was paying attention before and
20:54this is this is something that due to
20:57the difficulties in determining that
20:59and having the assays but eventually
21:02right now there is a major concern.
21:05So in terms of toxicity in general
21:08most of the toxicity what we know
21:10or what we knew and what we're going
21:13to do is from liver and kidney OK.
21:16But however they have been found that
21:18there is some effects also in nasal
21:21and eye liver toxist is dose dependent
21:25characterized by cell degeneration,
21:27preneoplastic lesion development,
21:30acid lobular swelling, necrosis,
21:33increased DNA synthesis,
21:35all the prenea plastic damages that
21:38you can see in chromosomal damage
21:41and and and enzyme leakage.
21:43The kidney toxicity manifests as a
21:46generation of the cortical tube cells,
21:48tubular tubular neclosis and
21:52chloro nephritis.
21:54So the other thing that we have
21:56discovered in our and which I think
21:59it could be very disturbing but is
22:01that we found out that there is
22:03a potential disruption of glucose
22:06homeostasis at least in our mice.
22:09But again, it's not published.
22:11We have it here.
22:14So the studies and I'm not going to go,
22:16I can bypass because time is running.
22:19There are a lot of,
22:20a lot of experiments both in mice
22:23and rats in over the two years that
22:26it is a proven liver carcinogen.
22:28And you know it has been shown
22:32that you know it is occurring in
22:35various labs throughout the year,
22:37throughout the globe and they
22:39found the same thing.
22:40So one of the thing though that it was
22:43a little bit puzzling is when they took,
22:46they did the genotoxicity.
22:47In other words they did the aims test
22:50or sister comma the exchange test.
22:52They couldn't find any genotoxicity
22:55for this 1.4 dioxin.
22:56So they said well it's not the mutagen,
22:58maybe it's a promoter.
22:59As you can see on the 4th bullet,
23:02well,
23:02there is a published study published
23:05last year by a Japanese group
23:07that indicates that 1.4 dioxin can
23:10induce DNA adducts as well.
23:13OK, and they're going on that.
23:16But what really triggered my interest
23:18and this is what really reflects
23:21essentially the mode of action of
23:241.4 dioxane is what they did is
23:28they took genotoxic carcinogens
23:31not genotoxic carcinogens in 1.4
23:34dioxane and they did the studies
23:36in both mice and rats.
23:37They measured the RNA sick and
23:40they try to make sense if 1.4
23:43dioxin belongs to one or the other
23:46group based on gene expression.
23:49And what they found as you can
23:50see from the from the slides
23:521.4 dioxin is a distinct form.
23:55So in other words it's it's does not
23:58belong to any of these two models
24:00which I thought it was very interesting
24:03and it was worth of exploring.
24:05So let's go and see what we're doing.
24:09So our Project 1 briefly goes
24:11on liver cancer and biomarkers.
24:14So essentially we're trying to use mouse
24:18models, human cells and organization,
24:21also zebra fish to dissect the
24:25molecular mechanisms of causing cancer.
24:27That's what the Project one does.
24:30The project Two, as I told you,
24:32there is no epidemiological study on,
24:35you know, on on 1.4 dioxin.
24:38And this was the major obstacle
24:40that I had to go through for the
24:43resubmission because everybody,
24:44when I was putting the stuff about
24:47carcinogenist, they said, well,
24:48we don't have epidemiological status.
24:50Well, somebody has to do it anyway.
24:53To make a Long story short,
24:54the budget of this project, it's not huge.
24:57So we did not have money to do
25:00the epidemiological studies.
25:02However, the NIHS said we do want
25:04you to do something about it.
25:06So what we decided was exposure assessment.
25:10So in other words epidemiological
25:13studies in much less number of samples.
25:17So the Project 3 is something
25:19that we're trying to detect the
25:221.4 dioxin and Co contaminants
25:24in areas that they're there.
25:26My whole idea in here is can we
25:29develop a system that it can be
25:32online that you can monitor the area,
25:35do the bio monitoring from your computer
25:38or the EPA can you know get the information.
25:42It's a difficult task.
25:45Many eliminated Jordan patio
25:46that when I talked to them about
25:48they said I cannot be done.
25:50Anyway, to make a Long story short,
25:52I'll show you what we're doing
25:53and we're trying to develop that,
25:54but the the idea of having those
25:57sensors is really hot right now in
26:00all the aspects that you can do.
26:02Finally, the project for as I told you,
26:04and this is another very important project,
26:07is how we can degrade.
26:10So you're well watered,
26:12most likely might have 1.4 dioxide.
26:15I'm not saying it does,
26:16but if it does, how you can purify it?
26:19Well, you can purify it with reverse osmosis,
26:22but do you have $15,000 to?
26:24So it's just for reduce versus
26:26Moses on your water.
26:28And some people may afford it,
26:30but how about the people that they cannot?
26:31We're talking about environmental
26:33justice as well.
26:34So there's a lot of issues that
26:36need to be discussing there.
26:37So that's Project 4.
26:40And the Project 4,
26:42essentially what it tries to
26:43do is trying to use what we
26:46call advanced oxidation,
26:47which is essentially oxidative stress.
26:49And I have more slides to show you,
26:51but I want to give you the big picture.
26:53So you try to utilize hydrogen peroxide,
26:56you break the hydrogen peroxide,
26:58you create reactive oxygen species
27:00and then the reactive oxygen species
27:03that can degrade your chemical.
27:05And this is also we're trying to do
27:08something similar with PFS as well.
27:10But anyway, this is of the record.
27:11Let's go for
27:15project One.
27:15This is the theme that we have.
27:17Essentially Yin Chen leads that I'm
27:20a Co leader, but I'm following her.
27:23That's her project.
27:25And we have of course Georgia from
27:27from and other people in the lab.
27:30And this is in collaboration
27:31with the National Toxicology
27:33Program with Stephen Ferguson,
27:35who is doing the human
27:38Hepatocytes and also the human,
27:41the 3D structures of the of
27:43the of the human cells that we
27:45can do the organoids and we
27:47can test 1.4 dioxin in there.
27:49So what we do here at the
27:51Yale and I'll show you is,
27:53is we're doing the mouse work.
27:55So NTP,
27:56National Toxicology Program is helping
27:58us with determining the effects on cells.
28:02And Robin Tanway from Ohio State University,
28:05which I was there 10 days ago,
28:07they're evaluating our 1.4 dioxin but
28:11most importantly the mixtures with the
28:14other Co contaminants on zebrafish.
28:16Why we do that because to do that
28:19in mice you need you know about
28:2320 fold budget and much more
28:27time to evaluate that in mice.
28:30So zebrafish in an is an amazing
28:33tool and actually his here facility
28:37up in Oregon State for the zebra
28:39fish screening and especially the
28:41exposomic studies is truly amazing.
28:43So we take advantage of that and
28:46actually we're not restricting the
28:48science only to carcinogenicity,
28:50but we're also doing a lot of stuff
28:53for behavioral stuff and also
28:55for that could have an effect on
28:58mental issues of this compound.
29:00So what we really know again
29:03this is I'm going to pass,
29:05I have covered that quite a bit.
29:07We know that causes cancer.
29:08We don't know the mechanism 1.4
29:11dioxin is a carcinogen in mice.
29:14We don't know what what is
29:16doing and what is going on.
29:17So what we're doing,
29:19so we're doing animal study,
29:21we're not just repeating what
29:23it has been done before,
29:25but we're trying to use knockout animal
29:27models that will have an effect on on this.
29:31So we're using models on oxidative stress
29:35and I will give you the examples in here.
29:37But essentially the first part is we're
29:40using mice and we do high dose and low dose.
29:44For the high dose is to get the effect,
29:46low dose is to mimic the human exposures.
29:49And from there we're doing the
29:52Omics based system approach,
29:53we're doing the RNA transcriptome,
29:56the metabolomics and also the
29:58phenotyping of this mice and we
30:01have quite a bit of data so far.
30:03So then we'll combine this on using
30:06deep learning, doing the RNA 6,
30:09the metabolomics and you know
30:11also the clinical,
30:12the not clinical,
30:13the phenotyping things and we're trying
30:15to determine the mode of action,
30:17the MOA and also the exposure and
30:20toxicity biomarkers which we're
30:21going to feed the project to when
30:23they do the exposure analysis.
30:25I told you before that we also
30:28using the the HEPA RG cells with
30:32NTP and the zebra fish for the AM 3.
30:36Here is a little bit of
30:38of the what we know and what
30:41we're currently know regarding the
30:43the metabolism of 1.4 dioxane.
30:45One of the thing I want to take your
30:48I want to have your attention to it.
30:50It is metabolized by cytochrome P452U1.
30:53Why this is important?
30:55Because cytochrome P452U1 is the
30:59activator of many carcinogens,
31:01many what we call precarcinogens to
31:06very active intermediates that they can
31:08cause cancer that can interact with DNA.
31:10So as you can see on the right
31:12hand side you can see also you
31:15have the TCe and the PCE which have
31:17the solvents which can also be
31:20metabolized by cytochrome P452.
31:21I want you to keep that in mind
31:24because what we have found,
31:26it's something that I think we have
31:28explained some of these effects.
31:30So we've we've already
31:31published quite a few papers.
31:33In terms of the mechanism,
31:35I wish I had too much time to show you,
31:37but one of the major findings that
31:39we did and nobody has shown that
31:43before is we found that 1.4 dioxane
31:46induced the cytochrome P452E1.
31:50And why this is important?
31:52Because if you have a Co exposure of
31:56cytochrome P452E1 and trichloroethylene
31:58or diethyl nitrozamine in your
32:01cigarette smoke or in, you know,
32:03in the smoke food that you eat,
32:05then you have higher chances of
32:07metabolizing the procarcinosis to
32:09carcinosis and they can cause liver cancer.
32:12So in other words,
32:13it can act as a promoter by
32:16inducing the cytochrome P452E1 in
32:19addition to the cytochrome P452E1.
32:21And you can see it in your left.
32:23We find that there is increased
32:25oxidative stress as indicated with
32:27four hydroxynone anal and also with the
32:30increase of the quinone oxidoridactase,
32:32which is a gene involved in
32:35the antioxidant response.
32:39So I apologize this happens again.
32:43You know the the image becomes a little
32:46bit but what the highlights of our
32:49research are this and this happens to me.
32:51I don't know why this but I have
32:54another one that I can show you.
32:56But we have find out so far that there
32:58is a direct xenotoxic effect for
33:01dioxin that includes oxidative stress.
33:03We already published that in 2022.
33:05There is a dominant role of two one
33:08in the metabolism as we have found by
33:11metabolomics and also for the liver toxicity.
33:15But also we have not only
33:20the induction of 2 E one,
33:22we have found the 2nd mechanism which is
33:26completely independent of Cytochrome B452E1.
33:28How do we do that?
33:30We're using knockouts that they have not
33:33Cytochrome B451 and we determined that.
33:36So this is what we're doing.
33:38Specific aim one and specific aim 2
33:41is we're using knockout mice and again
33:45remember we have the metabolism here.
33:47As you can see Cytochrome B450 is
33:50metabolized the first two animal models,
33:53the GCLM knockout is a model of
33:57mice that has low glutathione
33:59levels so that animal model,
34:02it has low antioxidant capacity.
34:04Nerf 2 knockout model is the Nerf two
34:07is a transcription factor involved
34:10in all the genes involving
34:12done dioxidant response.
34:13So if the nerve 2 gets activated,
34:16your cell becomes really active.
34:20Against the insults and we try we
34:22you we're currently using that,
34:24we're doing the experiments and to do that.
34:27So we're also using the cytochrome P4
34:30phase E2E1 As I said we completed those
34:33studies actually and we're using the NQ
34:36one and also the aldehydehydrogenase 2.
34:38As you can see the Ald H2 could
34:41be involved in the last steps
34:43of the metabolism of that.
34:44And you know the Ald H2 is a gene that
34:48has it's highly polymorphic in a lot
34:51of individuals especially those in from
34:56the from Asian population quite a bit.
35:00So Project 2 is the exposure
35:03assessment team led by Co led by
35:06Nicole Diesel and Brian Litter.
35:09And we have also most of our people from
35:11our department in exposures Crystal,
35:13Pollet, Zhai and Lu.
35:15And also we have collaborators
35:17in North Carolina State,
35:19Joe Hoppin and and death of Nappy.
35:22And this as I told you is going
35:26to be an exposure model,
35:27exposure assessment model here
35:29in Long Island and we have
35:32already going through that.
35:34So the aims again is you go you
35:36collect the water you collect the
35:38blood from these people and then
35:41you're trying to also make much the
35:45the medical records and you're trying
35:47to do the exposure assessment and
35:49we're trying to interact all this this
35:52project as I told you as we're using
35:54metabolomics in this in this project
35:56and the metabolomics here will be
35:59coordinated with a metabolomics for
36:01the first program which is on the
36:041st specific aim which is in mice.
36:06The third project is led by many
36:11Elimelech from the school of the the
36:15Department of Chemical Environmental
36:17Engineering and also you know is Jordan
36:20Petia and true Gender are from this,
36:23from this group.
36:24And again what we're they're
36:26trying to do is they're trying to
36:28develop this kind of molecules,
36:30the eptomers or all this idea that it
36:33can bind to that and then it can be
36:37detected and then they can transmit that.
36:40It's stuff we're not going to
36:41accomplish in the first five years,
36:43but at least we can develop the sensors
36:46to develop and then we can try to find
36:48out how we can develop the network.
36:514th project,
36:51and I apologize,
36:52I'm trying to give to finish so we
36:54can have some time for discussion.
36:564th project is by Jai Hong Kim
36:58and John Faulkner.
36:59And as I told you this is relating
37:02to develop small devices that
37:04you can use in your house to get
37:07rid of 1.4 dioxide and they're
37:09using the advanced oxidation.
37:11It will take me about a lecture to
37:13explain you that but essentially I think
37:16I told you the principle is hydrogen
37:18peroxide generate hydroxy radical and
37:20this hydroxy radical will hit that.
37:22They are using actually two kind
37:24of approaches in there and I think
37:26I have they they are developing
37:29some nice some nice things and
37:32I'm going to tell put there share
37:34some that you can that
37:35we have made.
37:37We successfully synthesized the catalyst,
37:40the boron doped carbon catalyst
37:42shown here and fabricated
37:44hydrogen peroxide synthesis cell.
37:47We quickly discover that maintaining
37:49the performance in the real water
37:52metrics would be the key for success
37:54of this research to provide a
37:57system that can perform for a long
37:59period for a household application.
38:01We therefore developed a framework on
38:04how to optimize post electrolysis to
38:07enhance catalytic tolerance against
38:10impurities present in water and in to
38:13improve overall lifetime of the cell.
38:16We discovered that optimized pulsing
38:19sequence enabled improved long term
38:22hydrogen peroxide performance to
38:24nearly 300 hours and 35 times better
38:27than conventional electrolysis even
38:29in the presence of most detrimental
38:32impurities such as nickel and zinc.
38:35These findings make this cell closer
38:38to real world implementation for
38:41prolonged hydrogen peroxide synthesis and
38:44subsequent one for dioxane destruction.
38:48Let me share some recent progress.
38:50This is the second we have made
38:51we successfully synthesized the
38:56I'm sorry it was I thought it was
38:59as an. This is the second method
39:01destroy one for dioxane in specific
39:04aim too we explore the use of
39:07engineered gas phase nano bubbles.
39:10We perform extensive characterization
39:12of nano bubbles in solution with a
39:15focus on hydro thoradical generation
39:18and by performing a number of different
39:22characterization using degradation of hydro
39:24thoradical specific target compounds,
39:26electron paramagnetic resonance spectroscopy
39:29and a fluorescence based indicator.
39:32Through this phase of research we
39:35concluded that nano bubble induced or hydro
39:38thoradical generation is minimal if not all.
39:41But we will continue to study if there
39:43is an alternative way to enhance the
39:46non local enabled advanced workstation.
39:50So I alternative technology
39:52I wouldn't be able to tell you that. So
39:57that's why I sent my daughter my
39:59daughter's first year in governmental
40:01engineering in Boulder, Co.
40:03So the next is our the next is
40:05our community engagement core,
40:07which will have Iris,
40:09Kaminski and Andrea and Esposito.
40:11Call it Derry Woods,
40:13executive director of the Citizens
40:14Campaign of the Environment.
40:16And we, you know, she's very big,
40:19big in terms of community
40:21engagement and we're doing quite
40:23a bit in in community engagement.
40:25We're ready and we utilize community
40:28engagement actually to recruit
40:30people for the project too.
40:32This has been fascinating so far,
40:35but we're not staying only in
40:37Log Island or even Vermont.
40:40We're expanding in other areas too.
40:42So the other areas that I'm working
40:44right now and I will tell you is
40:46the New Hampshire in North Carolina,
40:48Michigan,
40:49and recently I have been engaged by Florida.
40:53Believe it or not,
40:55there is an area over there,
40:56Lake Mary,
40:57that has even 30,000 times higher
41:01levels of 1.4 dioxin in their surface water.
41:06Anyway,
41:06this is some of the stuff that
41:09we've already done and the publicity
41:11that the centre is getting and
41:12I have more and more,
41:14but I'm just leaving you that we're
41:16using that as a tool and we communicate,
41:18you know, people calling me in the office,
41:21they said we want to register
41:22for this study and you,
41:24they need more information.
41:25And this has not been studying
41:27only in Long Island.
41:29And you know, newspapers have taken
41:31the centre because of the importance,
41:33as I told you,
41:34of 1.4 dioxin discovered in many states.
41:37So we're getting a lot training component.
41:39I think I was smart on that.
41:41I took our Jordan,
41:44I mean I took Chris Judy.
41:46Chris,
41:47Judy is our esteemed director of
41:49a graduate program at way SPH.
41:51And also we have the engineer,
41:53a graduate program.
41:54And this too made a dream team
41:57and you know it had actually the
41:59best one of the best scores on the
42:02components they had almost 1012 on
42:05their application and Yin Chen is
42:08also part Co investigator on that.
42:11So the way building up training
42:14education capacity going from even
42:18under graduates with an R-25 that
42:21they have on training undergraduate
42:24students to MPH students and also
42:27PhD students and post doctoral.
42:29This is classic regular the schedule
42:33we're doing for the training of our PhD.
42:37Last but not least and I kept the
42:39picture in here of Peter Petuzzi,
42:42although he retired and he
42:43just stepped down right now,
42:45but I love Peter and that was another
42:48another dream team here of Hong Yu
42:51Zhao and Peter Petuzzi that they
42:53that they do the data management and
42:56analysis core team which essentially
42:58bring all the projects together.
43:00And I'm not going to go to all specific aims,
43:03but essentially it's coordination
43:05between projects and cores, fostering,
43:08data sharing and interoperability.
43:12So we're trying to develop all this
43:14cloud systems and finally and most
43:17importantly is data quality assurance,
43:21quality control and data integration.
43:23So this is huge and we get really good.
43:27So I am almost at my 45 minute mark and
43:33essentially what I would like to say,
43:36the establishment of our Yale Superfan
43:39Centre marks a significant milestone of
43:42our departmental commitment to addressing
43:45emerging contaminants linked to cancer.
43:48Our strategic plan includes the development
43:51of peripheral research project.
43:53We get the budget cut of almost 50%
43:55of our initial budget, not only us,
43:58everybody did because they withdrew some
44:00money from that project to support the
44:03climate change in a number of institutes.
44:06So what we're trying to do is we're
44:08trying to develop peripheral research
44:10projects for exposure assessment and
44:12various locations across United States,
44:15fostering international collaboration
44:16and broadening the impact of our work.
44:20We aim to strengthen the partnerships
44:23of course with Cancer Center,
44:25with the liver center, with diabetes Center,
44:28leveraging their expertise and
44:30resources for more comprehensive
44:33approach to our research in vendors.
44:37And as we advance,
44:38our focus will extend beyond the scope of of
44:43the 1.4 dioxin and the volatile compounds.
44:46And we try,
44:47I'm going to try to get more emerging
44:50contaminant with particular emphasis to PFAS.
44:54And actually PFAS is, you know,
44:59because of their ability
45:02to be endocrine disruptors,
45:04they have been linked now
45:07to obesity and diabetes.
45:09And as I told you before,
45:10we find something similar and
45:11there are a lot of interaction.
45:13Another thing about PFAS
45:15induces kidney cancer, OK,
45:17it's the major cancer that
45:19induces is kidney cancer.
45:21So what is the,
45:22you know,
45:22the interaction of this between them?
45:24This is something that we need to explore.
45:26So this expansion will involve in depth
45:29exploration between links and the PFAS
45:32especially as I told you kidney cancer
45:34and and and obesity bringing virus
45:37insight to the scientific community.
45:39I'm going to stop with that and I'm
45:41going to take questions and we're
45:43happy to discuss anything you wish.
45:51Yes, great. Thank you.
45:53I the whole project began
45:58with the involvement of the
46:00community alerting you to 1 dioxide.
46:02So at the Cancer Center,
46:05liver cancer is a priority.
46:06Cancer that is in the strategic
46:09plan given its increased rates in
46:11Connecticut as well as nationally.
46:14So I'd love to think about
46:16collaborations to how we can
46:18do more on the epidemiologic or
46:20clinical aspect and and link it,
46:22you know with patients coming in
46:24newly diagnosed with liver cancer.
46:26Could there be a case control study
46:28where water is collected from their
46:31home blood questionnaires and
46:32then have a a controlled sample.
46:34So there's so much opportunity.
46:36I think here
46:37that's what David said. That's why
46:39he invited me to give the talk here.
46:41We need to get this, Melinda,
46:42this is a very good point.
46:44If we can get more and actually, you know,
46:47we can explore the possibilities and
46:48if we have more blood samples of that,
46:51we can do much better, much, much more.
46:54And that's a very good point. Yes.
46:58Going to Long Island for Thanksgiving,
47:01get your water with you. Is
47:04there a safe like what do you recommend?
47:07What is there a brand of like bottled
47:09water that doesn't that's guaranteed to
47:11not be contaminated? Depends.
47:13Now listen, I mean there are
47:15there are areas in Long Island,
47:16there is this interactive map that you can
47:19find which areas they have high levels.
47:21But to be on the safe side, you know,
47:24I was going to say use public water,
47:27but this public water over
47:29there comes from well water.
47:30I don't know how the late status is,
47:33but it might not be a bad idea
47:34to use some bottled water.
47:39First of all, I want to echo on you
47:41and Melinda set because there are
47:44tremendous opportunities here that
47:45are aligned in many ways with the
47:48forthcoming Cancer Center strategic plan.
47:51I'd like to add to that education because
47:54you have cancer education programs running
47:58that are cancer connected education
48:00programs running that are complementary
48:03to our other training programs.
48:05The question for you though is you began with
48:09a a challenge from the state of Connecticut,
48:11but I noticed all the
48:12collaborations are out of state.
48:14Can you tell us more about how
48:16this work might impact our state
48:19and our catchment community?
48:23It's the same thing.
48:26There are
48:27certain areas that they have 1.4
48:29dioxane in the state of Connecticut.
48:32However, the state of Connecticut has
48:34taken very good care of the public water
48:38and their public water is pretty safe.
48:40You are as long as you are in public water,
48:43they're taking good care how it's
48:45going to have a major impact.
48:46It's going to have a major
48:48impact on on liver cancer.
48:50But you know the problem,
48:52it might not be completely here,
48:54but it has several aspects of you know,
49:00getting engaged with
49:04agencies, the state agencies addressing that.
49:07And as Melita said, there is an
49:09increased rate of of liver cancer,
49:11which brings the other point
49:12you were talking about.
49:13I also have AT32 program with the
49:17livers with psychiatry essentially.
49:20But it's my point of view is my other
49:23lab that I have is alcohol and cancer and
49:26I actually organized the International
49:29Conference on Alcohol and Cancer.
49:31So this is another area that I think
49:34the increased levels of alcohol
49:35consumption is a very good contributor
49:38and that along with obesity.
49:40So if you add another factor which is
49:431.4 dioxin even if it's in low levels
49:46for for example in the state of Connecticut,
49:49what we saw in here there is an
49:51increase of the Cytochrome P CN¥452.00.
49:54So if you get get that in combination
49:58with smoking nitrozamines or other
50:01exposures you can increase the rate
50:04of you know of of cancer in the area,
50:10right. Yes,
50:15well that's a good point.
50:18Listen, we have done a lot of risk evaluation
50:23risk for water sources in on wells water.
50:27I wouldn't say that 1.4 dioxin is
50:30that major concern because we know
50:31what the were the areas of 1.4 dioxin.
50:35My concern would have been more on the PFAS.
50:39So my recommendation is test
50:41your well water for PFAS,
50:44that's the only suggestion.
50:47I don't think in Connecticut we
50:49have that major issue of 1.4 dioxin.
50:59Well, if you test, that's a very good point.
51:01If you test it, if you test your well
51:04and it's positive for 1.4 dioxin,
51:06you don't have to wait for for
51:09Jihong Kim to develop these devices.
51:12What you do is you use plastic water,
51:14I mean plastic water from,
51:16you know, from bottles.
51:17Of course you can have some things
51:19from there, but it's at least safer.
51:22If you find that there is P fast,
51:24the P fast, you can filter them
51:26with charcoal and stuff like that.
51:28So there are devices that
51:30they're relatively cheap.
51:32But one of the things that I want to tell
51:34you is the importance of drinking water.
51:36Because you're going to drink,
51:38you may avoid drinking alcohol,
51:40you may avoid smoking cigarettes,
51:43but you're going to drink your water.
51:44Yes,
51:48you're safe,
51:51you're safe,
51:55You cover both of them.
51:59Well, the other thing is
52:01you know in terms of the,
52:03the Cancer Center is the liver
52:06center and also there is a high
52:09incidence of alcohol induced liver
52:11cancers and not only the liver
52:13cancer but also colorectal cancers.
52:15And the incidence of colorectal cancers
52:17are really high as well throughout
52:19not only the nation internationally
52:22and especially the early onsets.
52:32Yes,
52:34I think so. Yes.
52:37So thank you for the question.
52:39Usually the stages are, you know,
52:41you start from steatosis,
52:43you go to fibrosis,
52:44you go to cirrhosis and then
52:46some cases you know you go to
52:49a pater cellular carcinoma.
52:51It is possible that you can
52:53go without cirrhosis.
52:54Yes, I mean in animal models
52:58they go without any any
52:59signs of cirrhosis at all.
53:06But one of the problems, well,
53:07talking about the animals and
53:08humans and stuff like that,
53:10you know that alcohol,
53:12it is well known that causes
53:15liver cirrhosis, right?
53:16If you try to do the same thing in mice,
53:20there is no way you can do it.
53:21But you can take a mouse and you can
53:24put carbon to trichlorate for 3-4 weeks,
53:27you'll get cirrhosis 100%.
53:29So that's that's the the challenges
53:32that you have between animal models
53:34and human thing and that's what we're
53:36trying to to do the organoids as a
53:39complementary to to the mouse studies.
53:46All right. Thank you very much.