Articles, Blog

Taking It All In: Environmental toxins and your health — Longwood Seminar

September 1, 2019


Welcome. Welcome to our third
Longwood Seminar of 2016. I’m Gina Vild. I’m the Associate Dean for
Communications and External Relations at Harvard
Medical School. We’re going to have
a full house tonight, so may I ask you to please
move into the center so people who arrive late
can take the end seats and it doesn’t
disturb the speakers? Thank you so much. I’m happy to report that as
a result of your attendance, both through live
streaming and in person, this has been the most
successful Mini-Med School we have had to date. So I want to thank you. Your engagement is impressive
and it is certainly appreciated. Your completing the
evaluation forms helps us with our
planning going forward. I encourage you to please
complete the form tonight. That will guide us as we
go into the next year. Your help in
crowdsourcing the topics helped ensure these were
both timely and interesting to the community. And your engagement
in social media, Facebook, Twitter, and
Instagram has really helped expand knowledge
to the public. So I invite you to join our
conversation tonight on Twitter with #HMSMiniMed. I hope you’ll join us for our
last Mini-Med School Longwood Seminar on April 22nd. It’s the new old age. And we will learn all about how
our body ages, and importantly we’ll learn how
to keep it young. Certificates of completion
are available next week if you’ve attended three
or more Mini-Med Schools. If you can’t be here,
please send us your email address at the
email on the screen, and we’ll mail it out for you. Now tonight’s topic
on the seminar that you’ve all been
waiting for is Taking It All In, Environmental
Toxins and Your Health. Rachel Carson, who
you may know, she wrote in Silent Spring
one of the landmark books of the 20th century. If we are going to live so
intimately with chemicals, eating and drinking
them, taking them into the very
marrow of our bones, we had better know
something about their nature and their power. In 1962 with this
book, she sparked the modern
environmental movement. Silent Spring
introduced new ideas that rapidly became fodder
for public discussion. People began talking about
the effect of toxic chemicals, especially DDT. Their effect on wildlife,
our environment, and on human health began to be
questioned for the first time. We’ve learned a great deal
over the past 55 years about the interconnection
of nature and human health, yet thousands of
everyday products are made with chemicals. Clothing, cosmetics, toys, food
containers to name just a few. And we know that
many of the chemicals are not adequately regulated. Rachel Carson also wrote,
if we have concluded that we are being asked to
take senseless and frightening risks, we should
look about and see what other course is open to
us, and that is exactly what we’re going to do tonight. Tonight, Harvard scientists
who are experts on the nature and power of some common
environmental toxins, will help us see what other
course may be open to us. So let me introduce them. Monica Colaiacovo,
who is a professor in the Department of Genetics
at Harvard Medical School. Maitreyi Mazumdar is
an assistant professor of neurology at
Harvard Medical School, assistant professor in
environmental health at the Harvard TH Chan
School of Public Health, and a pediatric neurologist
at Boston Children’s Hospital. But first we’ll hear
from David Christiani, a professor of medicine
at Harvard Medical School. He is the Elkan Blout Professor
of Environmental Genetics, and the director of the
Harvard Education and Research Center at the Harvard TH
Chan School of Public Health. He is also a physician in
the Division of Pulmonology and Critical Care Medicine at
Massachusetts General Hospital. Doctor Christiani has
examined genetic factors that make people
susceptible to lung cancer. At Mass General,
he also researches environmental
conditions of the lung. He runs a landmark 35-year
study of respiratory diseases that has determined the rate
of loss in lung function among dust exposed workers. In 2012, President
Barack Obama appointed him to serve on the National
Cancer Advisory Board. Please welcome our
guest speakers. Thank you. Thank you all. Thank you all, good evening. It’s wonderful to see the
big turnout we have tonight. I’m going to use
environmental cancer as an example of
environmental conditions that are preventable, either
caused by the environment or to the extent that
we know, environment contributes to their
causes, which is a problem. But it’s also the
situation where there’s the opportunity for prevention. And so the title is Preventing
Environmental Causes of Cancer. There are only a few
slides that are technical, and I’m going to reduce
them very quickly to very understandable English. So I’m going to cover some
basic landmarks of what we call a cancer epidemiology,
the study of disease distribution and risk
in human populations. What’s known about
exposure and cancer? Why do we even make this link? And I’m going to touch
on a Presidential Report that had implications
for a global cancer health. The report was focused
on chemicals in cancer. And then talk a little
bit about the challenges that we face in
the 21st century. So what are the landmarks
in our understanding about how environment causes
cancer in human beings? In the 19th century,
cancer was somewhat unusual because people didn’t
live that long. And when it occurred, it was
generally considered incurable. 20th century, fast
forward to about mid part of the 20th century,
much of human epidemiology, particularly in Europe
and North America, shifted from the study of
infectious diseases, flu, pneumonia, diarrhea, to
chronic disease, ie now cancer. And then after World War
II, cardiovascular disease. So you can see this
epidemiologic shift in what causes morbidity
and mortality in countries across the world as we move
from infectious causes of death and perinatal and
childhood respiratory infection and diarrhea
to chronic disease. Well, cancer is one of
those chronic diseases. So exposures to
tobacco, diet, and some environmental chemicals–
so that was about the time when researchers first
entertained the possibility that cancer can be prevented
because we understand the cause. You can’t prevent something you
don’t understand the cause of. So the late 20th century, early
21st century where we are now, epidemiologic studies have
generated population-based data identifying risk
factors for cancer that may have multiple risk
factors, not a single risk factor. And the development
of new technologies to identify biological
molecules of exposure, to identify genetic
susceptibility, and creating different
deeper understanding of what causes it, and perhaps
also more opportunities for prevention. And that’s where we are today. Now cancer across the
world varies quite a bit. This is a busy slide, but all
you need to know is the colors. The red areas are very
high in certain cancers, and the green areas for
the same cancers are low. So in the case of cervical
and stomach cancer, it’s very high in certain
parts of the world where there’s not refrigeration. Lung cancer is very high
in the developed countries or industrialized
countries of the world, and those undergoing rapid
development like China. So any kind of color map
you use of cancer incidence varies a lot
according to exposures and the economic status of the
country which helps determine those exposures. Breast and prostate
cancer, for example, are much more common in people
in the industrialized world. And then if you
look here in the US, the number one cause of cancer
deaths in both men and women remains lung cancer. It’s starting to trend downward
because of smoking cessation efforts that started
as early as 1964 when you see there was
still a steep rise, but real serious attempts
to restrict smoking that came into place in
the ’70s and ’80s where it was banned workplaces,
public places, as you all know hotels, airplanes,
et cetera, then you start to see
exposure patterns, use patterns of
cigarettes decline. And then there’s a lag period. For a population to get sick
from environmental cancer, usually there’s about
a 20 year lag period from when an exposure is
introduced into the population. So for cigarette
smoking in the Britain, Great Britain, 20 years after
World War I you see this peak. US, it was around
World War II where there’s a big bump
in cigarette smoking and when women
started to smoke more. And then you see 20 years later. Well, it happens with
the other side too. When you start to see preventive
efforts be put into place, it takes a while
for the incidence to turn around and
start to come down, which is what you see there. This is women where
unfortunately lung cancer kills more women every year than the
combination of breast, ovary, and colon. And so it’s still and
will be the number one killer for a long time in
both genders in the US. Now I also want to touch
on environmental cancer. So the reason I talk
about smoking, by the way, is there was a strong
environmental causes of cancer, of lung cancer. We know what the cause is
even without teasing out all the chemicals
in lung cancer, and I’ll come back
to that in a minute. But you know that stopping
or cessation efforts leads to a decrease in incidence. So we’re able to, by
identifying and intervening, make a difference. Now childhood cancer, there’s
been a lot of debate about whether childhood cancer
is increasing in the US. It’s the second commonest
cause of death of children in the industrialized world. And about 10,000 to 11,000
kids are diagnosed in cancer probably pretty much every
year, and almost 1,600 will die. So just look at the line. If you look at the surveillance
data on children with cancer and do all the different
statistical adjustments over the decades of
’75 to 2008, there has been a gradual
increase in US mortality for all childhood cancers
under the age of 20. We don’t know why. We suspect environment
probably plays a role. This is just a pie chart
of the kinds of cancers that children get. By far leukemia and brain or
central nervous system tumors lead the pack with a variety
of very rare, much rarer ones in there. So what causes cancer? Why do we focus on
the environment? Well, there are a number
of external factors that give us opportunities to
intervene in cancer prevention. So one is industrial exposures. Almost everyone in
the room has probably heard of asbestos
and the problem that asbestos caused, and
has caused, and still is causing in parts of the world,
including the industrialized world. But there are many others. High exposures tended to
occur in workplaces because of the handling of
the material, less so in the general environment. But you can have
exposures to cancer causing agents in water,
soil, such as contamination with arsenic or
other carcinogens. Then of course there
are lifestyle exposures. They’re just as
environmental, but they involve personal choice,
whereas workplace would be an involuntary exposure
or in the general community. Tobacco use, diet,
physical inactivity, and in the case of
viruses, sexual activity can transmit carcinogens or
cancer causing agents that can then gain access to the body. Naturally occurring
exposures, and we should point out that not
everything natural is safe. So ionizing radiation,
ultraviolet light from the sun, radon,
arsenic, infectious agents, they’re natural, but
they’re also dangerous. Medical treatments not to be
underestimated these days. Chemotherapy, which cures
a lot of people every year, but the agents themselves
are carcinogens and they put treated people
at risk for second tumors. Radiation, immune
suppressing drugs all can be external
causes of cancer. Now there are also some
internal factors that are not easy to control, if at all. Genetic alterations,
hormone deficiencies, imbalances, immune deficiency. And some individuals are
more susceptible to cancer than others based on heritable
genetic traits we get from our parents, or
sometimes rare mutations that we don’t know
why they happen. And then there’s no other
way to talk about that other than bad luck. Or what we call co-morbidities. If you have one
disease, it’s not cancer but it’s an inflammatory
disease like inflammatory bowel disease, that
inflammation over time can put you at risk of cancer. So you have one condition
that’s non-cancer contributing to
cancer development, so-called co-morbidities. So let’s talk a little bit
about the history of exposures. The occupational exposures were
the most dramatic carcinogen experiences for human
beings with reference to it dating back
to the Renaissance. But the first known description
was by a Doctor Percival Pott in London who described
an unusual form of cancer of the scrotum of young boys
who were chimney sweeps. We’ve all read Charles Dickens. You suffered through Dickens
in your freshman year of high school. You know that the
conditions of the working class in Britain in the 18th
and 19th century was very bad. These kids were small and
they were up in the chimneys sweeping out coal, soot. In the soot he found
he didn’t know what was in it that caused cancer. He had no idea. But he just made the
connection between soot and getting into the folds
of the skin of the scrotum, and then had to teach
the kids how to wash, and they stopped getting
this kind of cancer. Every toxicology
course on cancer talks about the first
connection made between a definite external agent
and cancer in the literature. It took another
130 years before it was identified what it was
in the soot, the chemicals, the polycyclic aromatic
hydrocarbons that caused the cancer. In the 20th century, we had
many other examples because of the rise of industry. Asbestos, benzene,
coke ovens, things called amines, aromatic
amines, dyes, et cetera. And still today, more in
the industrializing world, occupational exposures
probably cause at least 6% of cancers in the
developed countries, and much more exposure
in the developing world. And so what Pott didn’t
know about in the soot that they found out in the
1930s and ’20s was there’s this group of compounds
that’s also in tobacco smoke. It’s in diesel exhaust. It’s an oil emissions
and coal emissions, and they’re called
polycyclics or PAHs. And we now know that those are
a very active bunch of compounds to not single one
that cause cancers, and not just lung cancer, not
just skin or scrotal cancer, but also bladder and gut cancer. And they’re in our
everyday environment, not just in the
chimneys of London or in the workplaces where
coal and oil is burned. So urban air
pollution is loaded. Wherever combustion
takes place is basically polycyclics released. There’s a steel plant in
China that’s obviously a polluted workplace, but these
are dormitories and buildings where people live right here. And so it’s a very intense
experience for them to live and work in
this steel industry. A lot of these are polycyclic
aromatic hydrocarbons that are cancer-rich compounds. Cigarette smoke has
it, plenty of them. And this tobacco
smoke carcinogens themselves are a
mixed group, and can cause a series of
reactions that can lead to damage to DNA,
and then mutation, and then cancers like
lung or bladder cancer. We looked at this in
a group of patients at Mass General as to why
young people who start smoking at a younger age are at
higher risk of getting cancer later in life than old people
who started at older age, and found that there
are more of these PAH bound to DNA in
individuals’ lung tissue if they started smoking
at a younger age than if they started
smoking at an older age. So it looks like it’s permanent
damage in the lung tissue that carries through
later in life. And we found that the
people with certain kinds of genetic variation
and metabolism are more susceptible to form
these so-called adducts, which are bonds, chemical bonds
to DNA in lung tissue. Finally, we also found when we
looked at blood versus lung, again this is a pretty
good correlation line that circulating blood
was a pretty good substitute, because we can’t get lung
tissue on people in population studies, was a pretty
good substitute for lung in measuring
these things. So urban industrial
air pollution, mainly of air but
also of water, are rich in these
kinds of compounds. We also, as another example,
took a very different tact, looked at leukemia in
children in Taiwan. Again, it’s a busy
slide, but I’m just going to point to this line
right here where we looked at children with leukemia. Their risk of having childhood
leukemia was about 54% higher if they lived within 1
kilometer of a petrochemical refinery than kids who lived
farther than 1 kilometer, adjusting for all other factors. So I wanted to touch
on the cancer panel just for the last
couple of minutes. The panel was
established in 1996 during Bill Clinton’s
reign to address frankly as possible key
issues in cancer. And each panel is done by topic,
and there are several experts who then go around the
country, interview experts, and talk to people in the field
and talk to community members about what concerns
them about cancer. And they did a
couple of reports. One was on lifestyle factors
associated with cancer, such as tobacco, and
the other was diet, and a third was inactivity. And in 2006, the panel was
asked to talk about chemicals in cancer, realizing that
these other issues have been dealt with. And so a committee
was convened, and they reported a fairly
hard hitting report that generated some controversy
because the committee was shocked when it reported
that 80,000 chemicals were on the market and only several
hundred had been tested, pre-tested for their
cancer potential. Since early ’70s, the
International Agency for Research on Cancer had
evaluated some 900 suspected carcinogens and found
that 165 turned out to be definite in human studies,
and another 265 as possible. And so this is a small
group of chemicals compared to what’s on the market. And so they criticize the
current regulatory approach in the US as evaluating
only when there’s evidence of possible
danger and setting standards only when there
is evidence of severe health effects, rather than a
cautionary or preventive approach. So they were a strong
letter to the president saying there’s a growing
body of evidence linking environmental
exposures to cancer, and the public is becoming
more aware and more concerned, is expressing the
concern, and that we need to do more about it. The panel highlighted a
number of things individuals can do to reduce their exposure
to potential carcinogens. This generated some controversy
because a lot of them had not been tested in trials,
although they are prudent, except for number five
which we all know, eliminating exposure to
secondhand smoke is important. So then the whole
issue of lifestyle versus environmental
risk come up. It’s impossible to
quantify these things. They’re both very important. So that some 45% percent
of cancer in the West is felt to be due to
either smoking, diet, or lack of exercise. But that leaves the other 55%
that we need to grapple with. How much of that is environment
is still up for grabs, except we know that probably
7% to 19% percent of that 55% is due to environmental
exposures. The thing to be careful
with all these percentages is sometimes they interact. You can have a lifestyle factor
and an environmental factor adding up to problem,
bigger problem, such as asbestos
like in this picture. And asbestos and
smoking together, rather than simply
add risk to 15, multiplies the risk
to greater than 50. So we have to do a lot to adjust
our environments to minimize exposures to
potential carcinogens. And some colleagues have raised
the concept of the exposome. We have the genome. We have metabolome. We have the exposome,
life-course exposure starting prenatally throughout life. What can we do to
minimize exposures to harmful agents
that cause conditions like cancer and others? So the challenge
in our studies are to do better exposure
assessment, where we can actually in
our population studies figure out what we’re exposed
to, when, and for how long so we can get better
estimates in our studies. So global cancer epidemiology–
this is what I want to end on. We should keep in mind that more
than half of new cancer cases and deaths each year now occur
in low to moderate income countries. It’s no longer just a disease
of industrialized nations. As infectious disease
comes under control, you see more chronic
illness like cancer and cardiovascular disease
causing mortality in the world. And the spread of the
so-called Western lifestyle is an important factor, but
also the exposure potential for industrial chemicals like
asbestos, benzene and silica. So we don’t want to have these
outdated assumptions of well, there’s exposures
we choose to have, the exposures we
don’t choose to have, and we can only control those
that are lifestyle factors. And we reject that just as the
president’s cancer panel did, that industrial
chemicals are still an important part of cancer
in much of the world, and we need to control cancer
by controlling these as well as controlling those caused
by tobacco, alcohol, diet, inactivity. They should be
complementary strategies. Finally, gene-environment
interactions. A lot of questions about
genetic susceptibility. Some tumors are due to
very rare mutations that are inherited, making
some people more or less susceptible to cancer. If they’re very
rare, sometimes it makes people very susceptible. But most of the
genetics we study, they make someone susceptible
only if they’re exposed. If we remove the exposure,
the genetic variant by itself is not harmful. Those are so-called common
variants rather than rare mutations. So the contributions of
environment to cancer remains underestimated. We know it’s a problem. It’s a bigger problem in
the rapidly industrialized countries of the world,
and it spanned the gamut of traditional exposures we’ve
known a lot about combined with new chemical exposures. And the contributions
of mixed exposures to cancer in both
work and community still remain relatively
poorly understood, and we need to leap in our
exposure assessment tools to get a handle on this so
we can prevent cancer rather than treat late stage cancer. So for clinicians, be more
aware of potential hazards. Use the databases online. Advise patients to
reduce exposures to what they can
control, smoking, diet, plastic containers, et cetera. So thank you. I will end there. So now it’s my to introduce
Doctor Monica Colaiacovo. Doctor Colaiacovo is a professor
in the Department of Genetics at Harvard Medical School. She studies how
environmental exposures impact biological
mechanisms that are critical to
reproductive health. She’s one of the nation’s
leading researchers in cell division
process of meiosis, which results in the
formation of eggs and sperm. And she has a rapid
screening process of how everyday
chemicals affect DNA that illustrates the
cost of an increasingly artificial environment and to
equip the world with accurate information to enhance
public awareness. Doctor Colaiacovo is
an associate editor in several key journals of the
world such as Genetics, Plus Genetics, and she’s a
recipient of a number of prizes in science, the most recent the
Harold Golden Lampert research award at Harvard
Medical School in 2013. So we’re very fortunate to
have her speak to us today. Monica? So I’d like to start by
thanking both Angela [INAUDIBLE] as well as Dean Vild
for the opportunity to be here and tell you a
little bit about our work. And thanks to David
for the introduction. So as you probably
already had a feeling for in this introduction, there
are various different chemicals in our environment. We’re only starting
to understand how they can impact health. And they can have
various different kinds of effects on health. And so in my laboratory,
what we’re interested in is understanding the
impact of these exposures on reproductive health. And that’s why the
title that I put up here says germline exposure to
our chemical landscape. We’re assessing the effects
and the mechanisms of function as a result of those exposures. And what I hope you can get
a hint of from this title is that because the
basis for reproduction, the formation of these
reproductive cells, egg and sperm, are happening
at a moment in time where it’s ethically and
technically impossible to look at this
directly in humans, we rely on the use of model
organisms to study this. The one that we’re focused
on in the lab are worms. And I will introduce you to
this model organism in a minute. So as I mentioned briefly
in the title introduction, meiosis is this specialized
cell division program that is the basis for reproduction. It’s the cell
division program that will allow you to form
the egg and the sperm. And the reason why meiosis is
different from a mitotic cell division is that at
the end of the day it results in the reduction
of the number of chromosomes that you have by half. And the reason why
you need this is so that the egg and the sperm,
which now carry only half the number of chromosomes
that other cells would have, when you undergo
fertilization, as shown here, you will be able to reconstitute
the right number of chromosomes in the new cell that is formed. But what we all
know is that meiosis is an imperfect process. There are problems
that can happen. There are errors
that can happen. And that will result
in the formation of cells that do not carry the
right number of chromosomes. And that’s what we
refer to as aneuploidy. The consequences of aneuploidy,
the formation of egg and sperm or embryos that don’t carry the
right number of chromosomes, can be severely deleterious
for reproductive health. And so on the next
couple of slides, I will introduce you to how
serious this problem can be. If you look at
the leading causes of infant deaths in
the United States, exemplified here as the
data for 2011 and 2012, what I hope you
can appreciate is that the leading
cause at the top here are congenital
malformations. And that is far
higher than something that we hear a lot more in
the news such as sudden infant death syndrome. It turns out that these
congenital malformations are a result of problems,
errors during meiosis. Not only that, 35%
of all clinically diagnosed miscarriages–
so this is probably an underestimate–
are due to errors during that process
of meiosis, as are 4% of all still births and birth
defects such as Down syndrome, trisomy of chromosome 21. And so it becomes
very, very important to understand not only
the genetic drivers of the process of meiosis, but
also the environmental impact on this process. And that became
very apparent to us because we were a
basic genetics lab. We were identifying
all these genes that are important for
the process of meiosis, so trying to understand what
drives this complex biological program. And then a few years ago
we realized we live also in a very complex environment. There are over
84,000 compounds that have already been produced. At least 1,000
additional compounds are added into the
environment every year. And when you look
into the literature and try to find out
how many of these have been tested for an
impact on reproductive health, it’s really very few. So we really do not understand
how these two are superimposed onto each other. We know that there are various
different exposures, agents, environmental factors,
that have been correlated with an impact
in reproductive health. For example, as mentioned
in the introduction, use of chemotherapeutic
agents, exposure to pesticides, plastics,
all the way to maternal age. And so we came up with
the following question in the lab, which is if
we want to understand the environmental
contributions to aneuploidy, to the formation of
these egg and sperm that don’t carry the right
number of chromosomes, can we use this roundworm–
it’s a microscopic model organism called Caenorhaditis
elegans– to investigate the impact of our
chemical landscape on reproductive health. And here’s a photo of the
team both past and present that are currently engaged
in this research in the lab. And so let me just remind
you really quickly about what happens during meiosis. So prior to entrance
into meiosis, your genome is fully replicated. Your duplicate all
the DNA that’s there. And then a series of
challenges start to come up. First, now you have these
two identical copies for every chromosome. They have to find each other
and pair with the right partner. We know that also there is
exchange of genetic information that takes place during meiosis. You basically swap bits of the
DNA between these chromosomes. That is why meiosis provides
for genetic diversity in the population. That’s why I don’t look the
same as David and David doesn’t look like my tray. So that’s why meiosis
is so important. And as you proceed
through meiosis, actually the
chromosomes are fully zipped up as well by a scaffold
that holds these chromosomes together. That zipper goes away. But now the chromosomes
remain attached because of the swapping of
that genetic information that took place. And now they’re under tension. So when these
microtubules that are like cables that
attach to chromosomes and then pull them apart
so that they can divide, when that happens, now
these identical chromosomes are separated apart. That’s the first
meiotic cell division. But what makes meiosis
very interesting is that you followed a single
round of DNA replication by two subsequent uninterrupted
rounds of cell division. So that now again this genetic
material, this blueprint gets split in half
through what’s called the second
meiotic division. And you end up with
the egg and sperm that now carry only half
the number of chromosomes. So the question, and I
hope you can appreciate from this simple cartoon, is
this is not a trivial process. There are many different
steps that can go wrong. And what we wanted
to ask is where can environmental exposures be
affecting any of these steps during meiosis. The model organism that
we use in the laboratory is this worm that
I’m showing you here. When it’s fully grown, it’s
about only one millimeter in length. And it offers a series of
advantages for those of us who want to look at what
happens in the germline. The first one I hope
you can appreciate from this movie which is that
it is a transparent organism. We can look at everything that’s
taking place inside this worm. And with the advent of things
like green fluorescent protein and so on, we can actually
look at specific tissues in real time and follow
what’s happening. This system also shares,
believe it or not, a tremendous amount of gene
conservation with humans. It turns out that anywhere
between 60% to 80% of all the genes in the worm
are also present in humans. And what I hope you can
appreciate from this cartoon is that 50 percent of
all the cells in the worm are contained in this
structure that I highlighted in blue, which is the germline. So for those of us want to look
at what happens in meiosis, 50% of everything in this
worm is undergoing the process that we want to focus on. If you dissect this
worm, if you cut it here and you isolate only one
of these two gonad arms, and you now stain chromosomes
so that you can look– imagine that this is a tube. It actually is. The nuclei are aligned on
the walls of this tube, and they’re moving. And what I hope you
can see is everything that’s in white here represent
chromosomes in these nuclei. And here I’m showing you
higher magnifications. You see a time course
of progression. You can see changes
as you proceed through the process of meiosis. And chromosomes organize
within these nuclei in very characteristic ways. And I should add, these
changes and how chromosomes are organized, they are
the same whether you’re looking in yeast, in worms,
in flies, or in humans. But what this allows
us to do is easily identify situations in which
you can perturb this process, where you’ve either affected
the timing with which things are progressing, or
the actual organization that these chromosomes acquire. And we use various different
markers and reagents to try to understand where
there might have been a problem. So when we started with
this in the laboratory, we chose to focus on a very
highly prevalent chemical that’s in the environment. And our compound of choice
was bisphenol A, or BPA, which many of you must
have heard a lot of. It’s highly prevalent
in the environment. It’s a very commonly
used plasticizer. Is in the inner lining of
cans because it protects the product in the can from
basically damaging the metal container. It’s present in dental sealants. It’s present in fabrics. So we are exposed
to it every day. It actually exhibits
an exergenic activity. It’s an endocrine disruptor. But it turned out that studies
that initially came from Japan show that there was an
association between the risk for miscarriages
with women who had a very high level of bisphenol
A either in their blood or their urine. And when they analyzed
the chromosomes for the miscarried
fetuses, what they found was that the number of
chromosomes were not normal. So remember, that’s aneuploidy. So they started to make a
correlation between perhaps high levels of bisphenol
A can result in a higher probability of miscarriage. And it was years later
that very elegant work done in a model organism, in
this case the mice, that they showed that indeed
exposure to bisphenol A can directly affect that very
basic process of meiosis, resulting in problems with how
those chromosomes are fully in line by that scaffold, the
synapses resulting in problems and aberrant morphology,
shape, and organization of the chromosomes, altering
the way that genetic swap of information, the
recombination process takes place, and
ultimately not allowing for an accurate partitioning
of the chromosomes when the cells divide. So here’s an image from
one of these papers that show you
chromosomes are in red. Those cables that are
pulling them apart, the microtubules are in green. And instead of having all the
chromosomes aligned right here, which is where they
should be, what you would see after a
bisphenol A exposure is some of these chromosomes
were not at the right position. And then subsequently when
you start repartitioning them, you’re not going to
distribute them properly. So this created a very
interesting situation for us, which is given that we already
knew what was happening in the mammalian
system, could we identify whether bisphenol A
caused a similar kind of effect in our model organism? But the second question was,
can we take it a step further? And perhaps because our system
is so easy to manipulate, can we identify the mechanism
by which bisphenol A is causing these problems? So can we identify the
meiotic stages and processes that are affected as well as
the genes and the pathways that are altered? Where is this bisphenol A going
to be working in this germline? And I’m going to just
really succinctly elaborate on some of the key
findings, which is that at a very high
concentration of exposure, one millimolar, this was the
equivalent of an intake of two parts per million. So what this was within the
range of the mouse studies that I just showed
you before, it was within the
range of people who, because of occupational
hazards, are exposed to high levels of plasticizers
or who manipulate cash register receipts, which are
coated with bisphenol A. So at that level of high
exposure, what we saw was a dramatic effect on the
fertility of these worms. So now they were unable to
lay normal numbers of eggs. There was a lot of sterility. And we also saw that the few
eggs that were laid, very, very few were able to hatch. And all of the eggs
hatched, those larvae never progressed into adults. So the impact of bisphenol
A exposure was very severe. And it resulted in exactly
the same phenotype, the same defects that had been
reported in the mouse model studies. We saw problems with
the ability of how things were getting
recombined, the ability to repair DNA damage. We saw problems with
the quality of how these chromosomes look like. We saw the fragmentations,
the aggregations. But in addition to
that when we looked at the first embryonic
cell division, and here’s an example of
what happens if you expose these worms only to ethanol,
which is what we were using to dissolve the bisphenol A, and
what happens if you expose them to bisphenol A. Again, in
green what you’re seeing are those cables that are going
to pull the chromosomes apart. In red are the chromosomes. Instead of nicely aligning
at this central position as it does in the
control, chromosomes never fully progressed. They didn’t quite
align properly. But more importantly,
and I hope you can see it indicated
by the yellow arrow, we started to see these
bridges, these connections that had never been resolved
between the chromosomes. And you can imagine that as
these masses are being pulled away from each other,
if they’re interlocked, you’re going to
mechanically damage them. And so this also explained a
lot of the embryonic lethality that we were seeing. We also saw formation
of abnormal spindles, which are these structures
at the tips here. And ultimately these
cells during mitosis we’re not capable of fully dividing. So we were detecting
problems in meiosis says that we’re getting carried
all the way into mitotic cell division and affecting
embryogenesis. But what was very critical
about these studies is that we also
found out that there was a conserved set of genes. There were specifically
three to four genes that are conserved and
present all the way to humans and that are very,
very important for DNA repair that were
not being expressed normally following bisphenol A exposure. This was the first time
that this was reported. A few years after that,
several mammalian studies reported the same finding, which
is that bisphenol A exposure is causing many of these
defects that I just described because you’re deregulating
how certain key genes that are important for repair to
be present at the right time at the right level. Their products are not there at
the right time and right level. So that also meant that we
could use this model organism to really tease apart the way
in which many of these chemicals might be impacting
reproductive health. And so one of the things that
we got interested in the lab is, OK, we can identify
a chemical that might affect reproduction. We can understand the mechanism
by which it’s doing this. Can we go bigger than this? Can we start looking at hundreds
of chemicals and really, in a very quick manner,
take advantage of the fact that this worm goes from an egg
to an adult in just three days, and then it lays 300 eggs? A single worm will lay 300 eggs. That set of eggs will
only take three days to become an adult again. So if you think
about the life cycle, it means that we can look at
multiple generations in a very, very short period of time. And it’s a very
amenable genetic system because you have hundreds of
offspring that you can look at. You have the power of numbers
as well in looking at an effect. Can we harness that? And this is a cost
effective system. We keep these worms in Petri
dishes in a regular incubator. It is highly predictive of
mammalian reproductive toxicity based on several other
studies that I’m not going to go into details today. Can we use this to screen
hundreds of other chemicals and identify those that might be
impacting reproductive health? And one way in which we’ve
been doing this in the lab is taking advantage of
another interesting feature of this model organism,
which is C. elegans exists in two flavors. They’re either
hermaphrodites, meaning they produce both egg and
sperm and can self-fertilize. They carry two copies
of the X chromosome. Or they can be males,
which carry just a single X chromosome. A self-fertilizing
hermaphrodite most of the time will only lay
hermaphroditic progeny. Males are very, very
rare in the population. Less than 0.2% of those eggs
are destined to become a male. And that’s because, if you
think about it, to become a male it means you carry
a single eggs, it means there must have been
an error in how chromosomes were partitioned. It means that you
generated either an oocyte or a sperm that simply did
not have an X chromosome. And when it matched
with let’s say it was an oocyte that
had no X chromosome and it got fertilized by
a sperm that carried an X, that’s how you recover
the single eggs. So males are very, very rare. But we know that if
you affect meiosis, you start to randomly
have problems. You start to randomly
partition these chromosomes. The frequency with which
you might have errors and how that X chromosome
gets partitioned goes up. And in fact, if you look
at meiotic mutations, we now start to
see 30%, 40% males in the population versus 0.2%. So it’s very easy to
detect something that’s messing up of with meiosis. So we could use
this, what is called a high incidence of males
output or phenotype as a readout to understand what chemicals
might be causing problems during meiosis. And that became even easier
because we could actually take advantage of the following. Barbara Myers lab
at UC Berkeley had identified something
called xol-1, X-O-L 1, which is a
male-specific promoter. That means it only drives
expression of a gene in males. She fused it to the green
fluorescent protein. N. Villanova at
Stanford University then used this construct, what
we call a reporter construct, in a very clever way. She thought, if I
mutagenize worms to identify actual
genetic mutants that might be important
for meiosis, and I have the worms carrying
this reporter construct, if I start to see more
males in the uterus, they will glow green. I know that those eggs are
destined to become a male. I must have hit something that’s
very important for meiosis because males are rare. So can I see these green
eggs in the uterus? And it turns out that
they’re very, very obvious. This is a snapshot of what
that uterus looks like. You can really see
these green eggs. And they would normally
never be there. So we then decided, well,
we can use this strategy in a slightly different way. What if we now use that same
reporter construct and expose our worms to chemicals? We can do this with
multi-well plates, so we have various
different chemicals, various different
concentrations. They’re swimming
in this liquid that has whatever toxic
agent we want to test. Can we then see if we
see these green eggs? And to make this even more
robust system, what we did is we introduced this genetic
mutation on a collagen gene called col-121. And the reason we did
that was to break down the cuticle barrier of the
worm so that we can really now introduce very,
very low concentrations of the chemicals. For example bisphenol
A, we can significantly dial down the concentration. It’s no longer 1 millimolar. It’s 100 micromolars. It’s very, very low. Now we can work within
the range of what’s used in cell culture experiments
and all these other systems. Can we see an effect? So can we see these green eggs? But to make it
high throughput, we can take advantage of still
another technological advance, which is that there
now is a machine that allows you to fact sort your
worms based on fluorescent. So you put these life
worms through this machine and it will detect
whether you’ve got green eggs in the
uterus or not and how many. So what’s the fold increase
compared to, for example, the vehicle alone? And so we’ve been successfully
applying this strategy. And I’m just going
to quickly show you a slide that exemplifies
the kind of library that we’ve been
investigating now in the lab. We’ve been looking
at components that are using hydraulic
fracturing, components that are used in the
processing of crude oil, various different pesticides
and antimicrobials, phthalates, which are highly prevalent
in the environment because of plastics, cosmetics,
what you spray on crops, shower
curtains, and it’s been working very successfully. We’ve been able to identify
which of these are causing problems in reproductive
health, and now we’re starting to investigate why
they’re causing such problems, because that’s the final step. We want to understand the
pathway, the mechanism by which they’re affecting this. And ultimately we
want to find out chemicals that might exhibit
trans-generational effects. So a single exposure
of mom that can lead to effects not only in the
children and the grandchildren, but in the great
grandchildren as well. So with that, if
there’s one important take home message that I
want to leave you with, it’s that we can start to
understand very important steps of this complex
biological program by taking advantage of
basic model organisms. This can inform what happens
in the human scenario. Questions that are
raised in humans can be answered by what
happens in the worm. So these can feedback
into each other. This is not perfect. You need a combination
of different systems to ultimately get a full picture
of what might be happening. But we hope that this is one
element in a cascade of things that might be used in
assessing what chemicals might be doing before they’re
delivered into the environment. And with that, I’ll thank the
lab as well as funding sources. Thank you. Thank you Monica. Last speaker before questions
is Doctor Maitreyi Mazumdar. Doctor Mazumdar is an
assistant professor of neurology at
the Harvard Medical School in Boston
Children’s Hospital where she’s an
assistant professor of pediatric neurology. And also she’s an
assistant professor in the Department of
Environmental Health at the Harvard TH Chan
School of Public Health. Her research focuses on
environmental exposures to compounds like arsenic
and neural tube defects like spina bifida. Her studies take
place in Bangladesh where there’s an estimated
70 million people who’ve been infected by arsenic
tainted drinking water. In 2016, Doctor Mazumdar
was the recipient of the Outstanding New
Environmental Science Award from the National
Institutes of Health. Thank you. This is quite a thrill. Thank you for inviting me
to participate in this. And I have to say this is great. You can’t hear me? Is the mic on now? Now it’s on? OK. Maybe it’s too far away? I want to get it
right because what’s the point if you can’t hear? All right, is it better now? OK. So I’m a pediatric
neurologist, and I’ve come to talk to you
about children, children and environmental chemicals. And I’ll just give
you a quick overview about what I’m going to cover. We’ll spend a little
bit of time talking about why kids might be more
vulnerable to environment environmental chemicals. I’ll use lead
poisoning as a paradigm to discuss developmental
neurotoxicity. Lead poisoning is in
the news these days. And I think in addition
to being a timely topic, it’s one that really has been
studied well and studied well in Boston in particular. And then the end with
just a plea as David has already mentioned about
a precautionary principal in our approach to
environmental chemicals. So why are kids different, or
why might be kids difference, or why might kids be more
vulnerable to the things that we’re talking about? And I think kids have a
number of different things they put them at higher risk. They have different
and unique exposures, which we’ll talk about,
different from adults. They have a physiology
that’s very dynamic. They’re growing,
and their growth provides windows
where they may be more susceptible to harmful
chemicals in the environment. They live longer, so
they have a longer chance to develop problems even from
an exposure early in life, and we’ll talk a
little bit about that. But I think most
importantly, they rely on us, they rely on adults
to protect them. They can’t make a lot of the
choices about where they live, or their lifestyle,
or what they eat, or what they’re exposed
to, or what’s regulated in their environment. They don’t vote. And so they are vulnerable
just because of there situation or their position
in our society. So let’s talk a little bit about
different and unique exposures. So in addition to
breathing the air and eating food and
drinking the water, children are exposed to
unique exposure pathways. They get chemicals
passed through them through the placenta, through
the umbilical cord, which can be a very
protective environment. The placenta often does
shield out a lot of chemicals, but it’s not perfect. They are exposed to chemicals
through breastfeeding, which is just a very different
way of getting exposure to a chemical in
the environment. They have exploratory behaviors
that are different from adults. They put things in their mounts. A train toy that we might
have on our desk, my son puts in his mouth. What can you do about that? So they are different. They have different stature
and micro environments. They’re shorter and
closer to the ground, so they’re closer to the carpets
that might have chemicals. They’re just there. We’re up here. They’re there. They breathe different air
because they’re shorter. What comes to them into
their respiratory passages may be different from
what comes there. And they don’t
understand danger. If you say don’t go over,
there it’s dangerous, that will be the first
place that they go. So children are different. And you have to think
about them differently when you’re designing
strategies to protect children. So some of these I’ve
already talked about, their breathing zones. Children are different
within themselves. A crawling child
might be more at risk than a child that
can be put in a crib unless the crib
itself is dangerous. Like I said before there,
they’re closer to the carpet. They also breathe more
air per surface area. For their weight, for their
built, they’re taking in more. They have a higher intake
of food for their weight, and they eat different things. So they have a different diet. They have milk maybe more. They may have different types of
things that are in their diet. I’m a pediatric neurologist,
so when I talk about children, I talk about children’s brains. And it’s just a model
of an organ that is undergoing development,
that’s growing very, very rapidly all the way
from the in utero period through adolescence. And as Monica mentioned
when she walked us through the steps of meiosis
and gamete formation, brain development is also a
very, very complicated process that has many places where
things could go wrong. So just to talk about
them or to highlight them, for the brain to develop, it has
to do many things in sequence in a very programmed,
very predictable way that involves many different
things, including genetic influences,
nutrition, but also can be disrupted by
chemicals or other things in the environment. So just to walk through
them a little bit, proliferation is the first step. The cells in the brain
have to multiply in number. Then the cells,
once they multiply, they have to travel to
where they’re going. So that’s a really exciting
part of brain development to study and to watch,
to see the brains form from the inside out. They start in the
middle of the brain, but then have to make their way
up to the ends of the brain. They form these connections,
which is called synaptogenesis. And then there’s also a
very predictable trimming of connections as well,
which is a natural part of brain development. It’s called pruning. Within that there is a very
sophisticated formation of transmitters and receptors. And all of these things
can be influenced by substances in
the environment, by experiences in the
environment as well. So children develop on a
very predictable course and in sequence. And so this is a slide from
Chuck Nelson’s group, who’s at Boston Children’s, showing
that within the first year of life there are developments
of vision and hearing pathways, followed by
language, followed then by higher cognitive function. And this is all related to brain
development in this pathway that these series of steps
that occur within the first 15 or so years of life. So why is that important to
what we’re talking about? Well, the reason I
went through that is because I wanted to make
the point of what happens to the brain of a person
who’s exposed to chemical can depend on where
in that process they are when they’re
exposed to the chemical. So this is a cartoon
from pathology from brain cuttings of a
population of Japanese people who were exposed to
mercury through dumping of industrial waste into a water
source and Minamata, which is an area in Japan, in the 1950s. And these are their brains
or cartoon of their brains in cross section. And if you look at the
adults who are here, children who were born after
the poisoning incidents, and the brains of children
who were in utero, whose mothers were pregnant
at the time of this poisoning, they were all exposed to
through drinking of water, though this population was
exposed transplacentally or in utero, you can see
that their pattern of injury is different. And so these dots are meant
to represent areas of injury. So in adults, the damage was
more focal, more restricted to certain parts of the brain. But in those who were
exposed prenatally or while they were
in utero, the damage was much more widespread. So just the age and
the developmental stage that these individuals were
at at the time of exposure affected how they
responded to this exposure. So that’s an overview
of developmental windows of toxicity, or why
I think children may be more susceptible. And now let’s talk about lead. And once again, there
are many chemicals in the environment that
we could talk about, but lead is really the paradigm
and also it’s very timely. So right now because of the
situation in Flint, Michigan, we’re learning a lot about
lead in the water and lead in water pipes. But it’s important to remember
that LED is really everywhere in the United States. And there are multiple sources
of exposure for children, even though it’s
improved substantially over the past decades. So in Flint, as
many of you know, there is lead in the water that
is related to leaded pipes. In Boston, the main
source of lead exposure is leaded paint from houses
that used lead paints prior to the ban of lead in the 1970s. And then every so
often there’s a story about lead in paint from toys
that are imported into the US. Prior to the removal
of lead from gasoline, lead in the air from
gasoline admissions was really the major source. And elevated blood
levels affect the brain, and we’ll talk about
that to some extent, but it really affects
every part of the body. At high levels, so
levels at about 100 or 150 micrograms per
deciliter, children used to die from lead
exposure, and still do in many parts of the
world, such as Nigeria where children are exposed
to lead in lead mines. We’ll talk a little bit
about developmental toxicity and the studies
that were done here in Boston where lead was shown
to be associated with decreased IQ, decreased hearing,
decreased growth, and other maybe less
dramatic but still substantial neurologic outcomes. Actually, even though
we’re talking about lead, the story of lead is really one
of our biggest public health successes. Blood lead
concentrations in the US have reduced dramatically
over the past decades. In the 1970s and 1980s, the
median blood concentration among children, median
lead blood concentration was around 15, which
is a level that would be considered completely
unacceptable by today’s standards. And now it’s less than 2. And this has to do
with restrictions on the use of lead-based
paint, and also the phasing out of leaded gasoline. But let’s talk about
what lead does. And we’ll talk a little
bit about studies that were done here at Boston
Children’s Hospital and just down the street. So in the 1980s, one of
the very first studies done to look at the effects
of childhood lead exposure showed that if you looked
at the teeth of children who were exposed to lead, if
you looked at children who had high levels of lead in
their teeth by some measure, and those that have low,
the IQ, the verbal IQ scores of the group with
lower lead levels were higher. So there was a drop in
IQ scores among children who had higher levels of
lead in their teeth, teeth being a measure of
chronic exposure. The number of IQ points
wasn’t very high. That change was around
4 IQ points, which may not seem like a big change. But if you look over a
population over a big period of time, these children who were
exposed to lead consistently were doing a little bit
worse than their peers who were not exposed to lead. This started a number of
studies, tens and twenties of studies all over the
world to look at lead and IQ. And you can see that the
results were really very varied with different estimates of
the effect, different shapes of their curves,
different ranges, both of IQ and of blood level. But when you sort of combine the
data and look at them together, you can see that there’s a
pattern that at lower blood level concentrations,
there’s a steep drop in IQ with this being sort
of a range of IQ. And as you go out, the shape
of this curve flattens out. So there’s certainly
effects of lead that are seen throughout
this range of exposure, but at the beginning,
at these lower levels is where maybe
a little bit of lead is the most harmful. This and these public
health interventions that I mentioned before has led
to a drop in the level of lead in the blood that we
consider to be harmful. Before we used to say that
a level over 60 was harmful and under that was probably OK. And then that threshold have
come down over the past set number of decades. When I was in medical school, it
was 25 and then reduced to 10. And now as we understand that
lower and lower levels of lead can still cause this drop
in IQ or other measures of neurologic function, we
don’t even call it a threshold anymore. We say it’s a reference
level, that there’s no level of lead that’s OK. And this level of 5,
which is the level that was used in Flint to identify
children with high levels, is still something
that we’re trying to get lower and lower
and lower every year. So those are the
effects on children. But are there effects
that last longer? How long do these effects last? So there’s certainly
a hypothesis that’s out there that children
who were exposed to lead, or exposure to
chemicals early in life, has not only effects
on the number of cells, or you can use this
as cognitive function of a number of different
outcomes on this y-axis. Not only do people who are
exposed to this chemical exposure early in life, so
this is let’s say prenatally, and then this is their lifespan. This would be
normal development. There’s some cognitive function
and then some normal decline. I’ve taken the ages off
here because I’m reaching the point of inflection. I don’t really want
to acknowledge that. But let’s say
you’re exposed here and then there is
a measurable change in your performance on tests
because of your exposure to lead. So this has been shown,
but there’s a hypothesis that it also causes a
decline, a more rapid decline as your age goes on. Now how would you test
that, though, in people? So in our studies, the ones
that I mentioned briefly, you can look at kids and
sort of get some estimate of their early life exposure
either through biomarkers or teeth or some other thing. But if you’re,
let’s say, 70 or 60, how do you estimate
what this exposure is? It’s really hard to do. This is a hard
hypothesis to test. So this is where we
often go to animal models because, like worms, they
have a shorter life span. And so there’s this very
interesting study that’s out there in the animal
literature– this is from mice, and this is a group in Rhode
Island– that gave lead to mice early in life. So this is their lifespan. And these are controls. So these are mice that
were treated with lead, and these were controls. And they were treated with
lead and they followed them through their life span,
which is about two years. And as they got older,
their expression of genes that are involved in
protein folding, genes that are involved in processes
that are similar to those of Alzheimer’s disease,
expression of those genes went up. And then later if you
looked at the neuropathology of these animals,
you could that they had more information of these
plaques and accumulations, I guess. There were more in
those that were treated with lead than those without. So the hypothesis from
the animal literature is that early life lead exposure
may be a risk for later life Alzheimer’s disease. So once again, it’s hard
to test that in humans. Let’s say I decided to start a
cohort now, or when I was 30, and then follow
them for 70 years. By the time it comes the time
to evaluate them, they’re 70 and I’m 100. So you can’t really do
very much about that. So we went back to our
cohorts of children who were born in
the ’70s and ’80s, and then we tried to see
what they were doing. And I’ll run through
this quickly. We saw that we were able to
get about 80 kids, 80 adults, 30-year-old adults
who we had information about their umbilical cord lead. And we saw that they still had
decrements in their IQ when compared to those who
were not exposed to lead. And we also saw,
using a biomarker for Alzheimer’s disease, where
lower levels is associated with a higher risk of
Alzheimer’s disease, we found that– let’s
just use this one– that those who had
higher cord blood lead concentration had lower
amounts, at least nothing in this area of these
particular proteins. So it’s an interesting
hypothesis. It’s one of many,
but it’s there. So what we think we
know– I’ll just end now. We know a lot about
lead, but we really don’t know much about
these other chemicals. And there are many chemicals
in the environment. Lead is a paradigm because
of its effects on the brain, because we have a lot
of literature about it. But there still are
these other things that we can use a similar
approach to study. And as David
mentioned, we should apply a precautionary
principal, and not wait to demonstrate that
these things cause harm or to see that they cause
harm, but especially in the case of children,
err on the side of caution. So our conclusion is that
children have heightened vulnerability because of
the developmental processes, because of their
position in society. And that lead
poisoning illustrates the developmental toxicity. There is increasing recognition
of effects at low levels. The effects are
long term and there may latent effects, such as an
increased risk of Alzheimer’s disease, and that we should
apply a precautionary principal for the introduction of
chemicals into the environment. And that’s it. Thank you, Maitreyi. We’re going to give people about
30 seconds to clear the room, and then we’ll start
with questions. Thank you for your questions. We have quite a few very
interesting questions that were written down. Excellent questions. OK, good. So we’ll start. OK, so we’ll start
with questions. The first two for
Monica Colaiacovo. One is, since human oocytes are
generated early in development, at what period do exposures
have their main effects? And for example, does
a mother exposed to BPA have risk of offspring with
aneuploidy, or do her children? So the process of
meiosis is happening inside that developing fetus. So if the mother gets
exposed, what’s happening is you’re affecting
the meiosis that’s taking place inside that baby. So ultimately, what
you’re doing is you’re affecting the quality,
for example, of the eggs that that child will
eventually produce. The impact is going to
be on the grandchild. So that child might have a
higher incidence of aneuploidy because it got exposed
while it was in utero. Having said that, meiosis is
a process that takes decades. It’s initiated in
that developing fetus. It’s then arrested. And then later as the
child reaches puberty, that’s when you start
to complete meiosis. So you’re in what’s
called diapause. You’re arrested at a
stage called diakinesis, and then you resume
meiosis and you complete it, which means that
additional exposures that can take place even in that now
adolescent woman, for example, can then impact the subsequent
end-tail steps of meiosis as well. So it’s not limited to
what happens in utero. You can have additional
exposures in your lifetime that can affect
things later as well. Thank you, ma’am. So one more, Monica, for you. There are actually many
in there about chemicals. But what about
those of us over 50, outside of our
reproductive window? Do we have to worry
about plastics? Should we throw out all
our plastic containers? So I focused a lot
on what happens in terms of reproductive
health, but yes, you need to be but aware
of the fact that exposure to this plasticizer
and plastics in general can have various different
deleterious effects. The exposure to bisphenol
A has been associated with cardiovascular disease,
with diabetes, with it possibly being what we call
an obesogen. It can be affecting the ability to
gain weight and be associated with the obesity epidemic
in the United States and other developing countries. So a couple of
things that people should be constantly aware
of is you do not want to heat plastic containers. Do not microwave anything
that has plastics. You do not want to, if you
can, put anything that’s plastic in a dishwasher
because of the high temperature that that will achieve. So you watch things
by hand and you have to use very,
very gentle detergents and try to use the
non-abrasive side of a sponge, for example, when you’re
cleaning the container because you don’t want to
facilitate leeching out from that plastic into
whatever you’re going to put in that container later. So that’s something
that you need to be very consistently aware
of, because the impact is not only about reproduction. And in the case of men who are
beyond where spermatogenesis is happening all the
time, this is an issue no matter what, even in
the context of reproduction in older men. So in my household, I basically
eliminated as much of plastics as I can, and I’m
very, very cautious about what I do or do not
put in contact with plastics. Thank you. Another question. Can being exposed,
not wearing a covering to protect you to x-rays
be harmful to you? The answer is yes. You should always be
protected with lead aprons or the equivalent,
basically lead aprons when you’re being x-rayed. It’s cumulative, however. A single time it happens
is unlikely to increase your risk a lot. It’s cumulative over many years. Another cancer question. You mentioned a lot of
carcinogenic substances. Which single one should
be targeted first? The obvious smoking. Well, actually it’s
a good question. You can go on to the EPA
website, Environmental Protection Agency
website and look at carcinogens, which is
similar to the International Agency for Research on Cancer. In the group that’s 1,
known human carcinogens, and 2a, probable
human carcinogens, the total is about
400 chemicals. Definitely 1 and 2a
should be avoided. Then there’s possible
and then there’s unknown. And so I think the list is
longer than you’d expect, beyond just things like smoking
and a few others I mentioned. But most of them are not
necessarily in everyday use. That’s why the EPA site
explains it a little better. Another question. Let’s get a lead question
for Maitreyi there. We dealt with microwaving. Literally everything is
made up of chemicals. How do you deal with
self-proclaimed scientists in social media who say
that any chemical that you can’t pronounce is dangerous? Actually, it’s a good question. In a way, and I’ll see what
Maitreyi and Monica feel about this, to say that
everything causes cancer, everything causes brain damage,
everything causes reproduction has a long name
is disempowering. It’s not empowering. We really want to
know a couple things. One is, not every
chemical is harmful. Of the 80,000 on the
market, I’m fully prepared to realize or understand that
the majority probably do not cause cancer or any
serious effects, but we just need to know. That’s the one thing. We have a right to know
what does and doesn’t cause, realizing perhaps the majority
do not cause any problems. Therefore you focus on the
ones that are the problems and become empowered to minimize
or eliminate those exposures. So when you think
about it, if you say, well, everything causes disease,
that’s very disempowering. Because what are
we supposed to do? So the facts, that’s why
we do scientific research to prioritize those things. All right, Maitreyi,
you’re not off the hook. Let me see. Water safety. Is it safe to drink
tap water in the US? Is filtered tap water
better than unfiltered? What about boiled tap water? Boiled. Boiling it like they do
in much of the world. Well, certainly tap
water is in the news. And I think I might need
help with this from David. I think it depends on
the region where you are. And I think this is
an example of how different areas and
different municipalities handle things differently. So I think in many
communities, the water that comes from the pipes and tap
water is probably very safe and is well treated and
cleaned without significant contamination with chemicals. But it is very area-dependent. I agree. And also, within an area there
is going to be some issues. Boston, we’re fortunate. The Quabbin Reservoir is
a very good water supply. However, we have conduits in
Boston that are very old pipes and can be leaded. So the water supply is
actually outstanding. But when it cuts to
the house, if you have lead pipes, conduits in
the house or aging lead pipes, then that house can have a
problem or the group of houses. So I agree with Maitreyi. It’s regional, but
it’s also very local. And so it is worth thinking
about looking at your locale, what’s been known
about it and what testing you may have to do. Finally, boiling water is
done in a lot of the world to avoid infectious
contaminants. We never really recommend that. So think about high
school chemistry. If you’re worried about
metals and you boil the water, what happens? You concentrate the metals. Because you’re
boiling off steam. You’re letting those nice
water molecules go away and you’re concentrating
lead, arsenic, or manganese. There’s no reason to
boil it in the US, although there may be situations
where the water is not safe. And the other thing
is bottled water. There was a study done
some 20 years ago of some of the popular
bottled waters around, and they had higher
levels of contaminants than the municipal
water supplies in places like New York and Boston. So certainly be aware of it. Now with the Internet you
can get a lot of information on your local water supply. OK, next question. Series of questions. Is secondhand smoke
still a problem? Yes, but it’s
declined a lot because of regulatory and
educational efforts. Secondhand smoke, a spouse
living with a smoking spouse has about a 30% increased
risk of getting lung cancer. So your spouse is the
number one target. But in terms of the workplace
and the general environment, there has been in the US I
think significant, really significant progress in this. PCBs. There’s a question about
PCBs in a site in Hyde Park. The company wants to put them
underground and vaporize them. They probably want
to incinerate them is what it is, which is
what happens sometimes at Superfund sites. That sounds weird, but
sometimes high temperature burn for certain organic
chemicals is actually one of the ways of remediating it. It’s not that they just
take the chemicals. It’s the soil
that’s contaminated. And so they basically burn
the entire several feet or whatever the hydrogeology
and the environmental engineers say you need to go down
to get to clean soil. And so that is still an
acceptable environmental engineering procedure,
realizing that the controls on their emissions have to be
quite strict and the latest technology. Lead in chocolate and
arsenic in bottled water. Maitreyi? So I don’t know about
lead in chocolate. I think the issue about
lead in food products, however, is certainly
one to talk about. In the US, food
and food products, at least when it
comes to metals, are quite well regulated, or
at least that’s my opinion. In the rest of the world and
the rest of the developing world especially, lead
is used as something to brighten the
colors, to increase the weight for spices
and other things that are sold by the weight. And so lead contamination
of food products and spices is a very big issue. We, both David and I were
both involved in a study not very long ago where
the US had recalled batches of turmeric that had been
shipped to the United States because their own testing–
so they do testing fairly regularly of imports– had
shown very high levels of lead in these food products. And in the sites where
we work in Bangladesh, we found that we had high levels
of lead among the children. We didn’t really know
where it was coming from. We went to their homes and
we tested a number of things, including their turmeric. And we found
astronomically high levels of lead, which has no
role except it’s probably part of a dye to make this
orange spice more orange, because there’s no reason
to think that it would be in the ground or the soil. So whereas I don’t think it’s a
big issue in the United States, I think contamination by
metals and other chemicals in the food by lead is
increasingly recognized as a health hazard to children. Great. Another one for you, Maitreyi. How does medication affect
using for attention deficit disorder affect children’s
brain long term? So attention deficit disorder
is a particular diagnosis, one also that has a body
of literature relating it to lead exposure, early life
exposure, which is an aside, and not really the answer
to this particular question. So the medicines that are used
to treat attention deficit disorder generally are
a class of medications called stimulants, not unlike
the coffee and the soda that we as adults use to
increase our concentration. And the long term
effects on children, one, they’re short acting
drugs, so they don’t accumulate in
the body like some of these other chemicals do. But the long term effects
of these medications are related to the side effects
of the medication, which include decreased appetite. So when we think about
what the long term effects of these
medications are, it’s more to do with reduced
appetite and reduced food intake relating to
slower growth, which has been shown to reverse when
you take the medications away and kids get hungrier
again and then eat again. So I think in terms of
accumulating damage, there’s not evidence for
that in the literature. OK, a couple more
cancer questions. What, if any, toxins contribute
to skin cancer, melanoma. Actually, it’s
not so much toxins except arsenic can
cause skin cancer. There are some hot spots in the
country, New Hampshire water supply and some other
parts of the Southwest. But mainly skin cancer
is ionizing radiation, ultraviolet light problem here. So that means sunbathing,
tanning booths. Really I think tanning booths
should be banned, frankly. Should we limit dental
x-rays and MRIs? Medical x-rays should be
limited, as we mentioned, to the extent possible. You need them. You get them, but you have
your thyroid and other parts of the body covered
with a lead apron. MRI contrast do not emit
any ionizing radiation, so there’s not a
cancer risk for MRI. Why do children of a
high risk of leukemia? Actually, I might have
given you a misimpression. It’s not that they
have a high incidence. It’s actually these tumors
are rare in children. It’s just when they
get it, they’re grouped into these big
categories, and leukemia’s one, and it’s probably disordered
immune system from pre-birth. And so it’s not really that
they have a high incidence, it’s just that when
they do get cancer, they tend to group into
these categories, leukemia being a big one and central
nervous system being another. How can we prevent
these chemicals from ending up in our products? So that’s a policy question. So we’re scientists here. We’re trying to provide the
knowledge base which should then be translated into action. Some of that action is policy
on the part of government to regulate these
things so that they don’t get into
consumer products, into our homes and workplaces. And the other part
of translating scientific information is to
have the public be informed, because sometimes these
chemical compounds can’t be totally eliminated,
but need to be avoided. So I think it’s
a great question. And it differs a
lot where you live. The European Union
tends to be much tougher using the
precautionary principal than we are in terms of
the amount of evidence needed to ban a compound. It’s actually quite hard
to ban compounds in the US. But that’s why we do this work. We got a couple more minutes. I’ve observed the people
who are heavy smokers rarely live beyond the age of 60. Yeah, not much more
can be said about that. I think it’s a very
astute comment. It’s a sad one. And it’s obvious what needs
to be done to control that. The good news about
that, by the way, say you’ve smoked for 20 years. And you say, OK, it’s too
late, I’m already too far gone. Not true. You stop smoking, your
risk of lung cancer goes down 50% over
the next two years. So when someone
says that, just say, wow, you’re really a
fatalist, because you still can do something about this. If a person has a
blood transfusion, can they get cancer? No. Serious question,
and it’s actually no is the answer because you
usually get red blood cells. The blood has been treated. Cancer cells, even
circulating cancer cells occur in very low frequency
in the blood of patients with cancer, although
they do occur, but it’s not a
transmissible disease. At least theoretically, even
if one cell got through, your immune system
would take care of it. It’s a very good
question, but we’re not talking about infection. All right, so I
see the red light. I think we got through as
many of these as possible. Thank you all so
much for coming.

5 Comments

  • Reply jim dee March 8, 2018 at 8:28 am

    did they put a brown alien lizard on the front seat row ? or just someone with a big neck tumor ?

  • Reply jim dee March 8, 2018 at 8:48 am

    sudden infant death, maybe euh…. all those F-ing vaccines they poison the child with, starting at birth, or the flame retardants in the mattrras ? or the soy/rice/cow's milk allergy ?

  • Reply jim dee March 8, 2018 at 9:39 am

    at 1h26m, is this woman for real ? ADHD meds have FLUOR in them… kills the brain, the thyroid, makes them suicidal, but she does not think it is a problem ? studies have shown if you are 3-5 years on these meds, your chance to become bipolar just doubled ! sudden death on the sports field is also linked to this as it kills the liver, the heart, etc…

  • Reply jim dee March 8, 2018 at 9:43 am

    at the end, seriously ? cancer not in blood ? what about freaking SV 40 vaccine infected with 40 tumor / cancer causing agents….

  • Reply Martina P May 6, 2018 at 7:59 pm

    Lead? Are we in medieval
    Ages?? How about aluminum and mercury in vaccines! You are Harvard professors and good for nothing.

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