Food crops such as peanuts, corn, and wheat are susceptible to contamination
by molds – Aspergillus flavus and Aspergillus parasiticus. Aflatoxin, a
byproduct of these molds, is a potent cancer-causing agent. Long-term exposure
to aflatoxin has been linked to increased incidence of liver cancer.
Click on the buttons on the left to find out more about this carcinogen and its
link to cancer development.
Aflatoxin
In 1960, mold-contaminated peanut meal was shipped from Brazil to England and
fed to millions of turkeys, which in turn died of liver toxicity. Aflatoxin – a
byproduct of the contaminating molds – was isolated and identified as the
cause of the turkey deaths, and has been shown to cause liver cancer in other
animals. Today, strict guidelines are in place to regulate the levels of
aflatoxin in the U.S. food supply.
Click the forward arrow or the numbers below to find out more about aflatoxin.
John Groopman, Ph.D. is the Chair of the Department of Environmental Health Sciences
at John Hopkins Bloomburg School of Public Health. His research focuses on the
molecular causes and effects of environmental factors that may lead to the development
of cancers. This research has led to the development of biomarkers used in studies
of high-risk aflatoxin-hepatitis B populations specifically in China.
Aflatoxin is produced by a variety of molds and these molds contaminate the grains
either outside or they can actually penetrate inside the grain and aflatoxin
itself is a metabolite, it’s a product the mold produces that is then excreted
out and contaminates the grain. The toxicity of aflatoxin and its potency as
a carcinogen was recognized very early in the 1960s and as a consequence the
U.S. Food and Drug Administration and the U.S. Department of Agriculture put
in place regulations very early on in the studies of this compound to regulate
the levels of aflatoxin that would be permitted in the food supply. It was further
recognized that just the physical examination of a corn grain product or peanut
butter, or a peanut product was inadequate to determine if aflatoxin was present
and only a specific chemical analysis of the grain or grain product could be
performed to determine if aflatoxin was really there.
Thomas Kensler, Ph.D. is a professor at John Hopkins Bloomburg School of Public
Health. His research focuses on the molecular mechanisms involved in the development
of cancers linked to exposure to environmental carcinogens. This research has
led to potential chemopreventative strategies for liver cancer in populations
at high risk for aflatoxin exposure.
Aflatoxin is a very lipid soluble molecule so that when we ingest it, it's rapidly
absorbed. And it goes first to the liver where there are enzymes that will chemically
biotransform it into a very reactive chemical, which attacks with very high preference,
our DNA, causing damage to that DNA, mutations, perhaps in genes that enhance
our susceptibility to cancer production. Aflatoxin is also a very cytotoxic molecule
so it will directly kill some of our liver cells creating a void, if you will,
that causes the remaining liver cells to replicate and perhaps grow at a faster
rate than we would like. The combination of DNA damage and cell proliferation
triggers the liver cancer process.
Incidence
Mold-contaminated crops can be a serious problem especially in countries where
proper storage facilities are limited. In such agricultural communities,
exposure to the mold byproduct – aflatoxin – can be long-term, and
can happen through crop handling as well as diet.
Long-term exposure to aflatoxin and infection with the hepatitis B virus are
the leading causes of liver cancer. Click the forward arrow below to find
out more about the world-wide incidence of liver cancer.
John Groopman, Ph.D
Bloomberg School of Public Heath
Liver cancer is the third leading cause of cancer death in the world, upwards
of a million people die of liver cancer each year worldwide. Many of these cases
of liver cancer are in eastern Asia and Sub-Saharan Africa.
Early epidemiological studies demonstrated that the food supply in areas of the
world that had high levels of liver cancer were also areas of the world where
staple foods were heavily contaminated with aflatoxin.
We were able to do a large epidemiologic study involving many different collaborators,
many different research investigators where we examined over 18,000 people in
eastern China who were healthy at the beginning of the study, and as these people
began to develop liver cancer we then began to ask questions about what were
the factors in their diet or in their other exposure situations that contributed
to disease.
From this investigation we were able to find that both aflatoxin and the hepatitis
B virus separately were major risk factors for the development of liver cancer,
but in those individuals who were exposed to both factors together, there was
a very powerful, multiple interaction leading to extremely high risk for the
development of liver cancer.
We have a very effective vaccine against the hepatitis B virus, but because the
transmission of this virus occurs very early in life, we need to have the resources
and the ability to vaccinate the world for the rest of 21st century in order
to eliminate this virus as a factor in liver cancer development. Our studies
also showed that aflatoxin contributes to the development of liver cancer. And
it contributes to the development of liver cancer as a consequence of children
who once they are no longer being breastfed start to consume the normal everyday
adult diet. And so, the studies that we did that showed that there was this very
powerful multiplicative interaction between the virus and aflatoxin, indicated
to us that if we could block aflatoxin as a major factor in the development of
liver cancer, we would be able to lower risk of individuals. At the same time,
there needs to be the public health wherewithal in order to vaccinate populations
as the birth rate of a country moves forward. Simply put, there are almost three
billion people in the world who are at risk for the development of hepatitis
B virus infection. And the economic resources do not exist right now for doing
the types of vaccinations that need to be done for all the children who are being
born year in and year out. And so, this is one of the big public health challenges
that even when we have an effective vaccine you still need the economic resources
for vaccination and distribution.
Aflatoxin Action
Aflatoxin is a byproduct of mold that can cause DNA damage. With prolonged
exposure to aflatoxin, cells accumulate DNA mutations and thus are at increased
risk of developing into cancer cells.
Click the forward arrow below to find out more about how aflatoxin damages DNA.
Thomas Kensler, Ph.D
Bloomberg School of Public Health
A lot is known about the mechanisms of activation and action of aflatoxin. It
forms a reactive epoxide intermediate, which then forms a covalent bond to the
N7 atom of guanine in site-specific sequences within critical target genes leading
to mutations, altered function, loss of function of those genes. p53 is a major
target for aflatoxin.
Guanine
Aflatoxin
Aflatoxin is probably the best example of a carcinogen, a human carcinogen that
targets p53. There are multiple hot spots in the p53 gene targeted by different
types of carcinogens. Aflatoxin targets a guanine in codon 249 in the p53 gene.
I believe the importance of aflatoxin and the causation of liver cancer results
from a life long series of exposures. Intermittent sort of random exposures are
not likely to sort of tip the balance and create the cancer cells; our defense
mechanisms are pretty good for those very low levels and intermittent levels
of exposure. But there is a chronic long-term exposure through the diet in many
of these high-risk areas. In turn that means we need a chronic long term commitment
to a preventive intervention. We need an intervention that people could take
every day or at least several times a week, but not just for weeks to make the
problem go away, but for the rest of their lives. For as long as the aflatoxin
exposure is there, the need for the countermanding or intervention approach is
also very important.
Prevention
Limiting long-term exposure to aflatoxin – a mold byproduct – can
decrease the risk of liver cancer.
Scientists are also investigating the use of inexpensive, safe substances that
can block the damaging effects of aflatoxin.
Click on the forward arrow to find out how a chlorophyll derivative can block
aflatoxin action.
We’ve been investigating several approaches to try and reduce the impact
of unavoidable exposures to aflatoxin. One of our approaches has been to use
chlorophyllin, which is a derivative, simple derivative of the pigment chlorophyll,
which makes our trees green.
Chlorophylin
It's actually related to the molecule heme. It's a perforin-like molecule with
a metal complexed in the middle of it, in this case it's copper, but it forms
ionic charge interactions with planar molecules of which aflatoxin is a good
example. So there's ionic bonding between the two.
And the way we believe this molecule works is to actually intercept or form a
molecular complex with aflatoxin within our gastrointestinal tract. So, the chlorophyllin
and the aflatoxin bind each other up, get passed down the fecal stream. The aflatoxin
is never absorbed, never gets to the liver, never initiates the damage that creates
our problems.
We believe that if we can increase the consumption of leafy green vegetables
in particular, those that are rich in chlorophyll, that we might be able to reduce
the amount of aflatoxin that is absorbed.
It's worth pointing out that in our clinical trial we didn't use vegetables to
administer the chlorophyllin. We used tablets that contained 100 mg of chlorophyllin
and asked our participants to take one tablet 20 minutes before each meal. We
then measured for the presence of aflatoxin molecules in their blood and urine
and were able to show that those people who took the chlorophyllin tablet instead
of a placebo tablet had much lower levels of aflatoxin DNA damage products coming
out in their urine.
There is a lot of interest in discovering new classes of chemopreventative agents,
and foods, fruits, and vegetables in particular appear to be a very rich source.
So, we know of at a hundred natural compounds that work through the molecular
mechanism that we're trying to target – increased expression of detoxification
enzymes. But, there are many other compounds that work through other pathways
that also show great promise. And in fact, perhaps, the greatest promise will
come in combinatorial approaches where we take agents with distinct mechanisms
of action and put them together to really try and knock down the precancerous
cells.