Biology of Toxins Final Presentation
Spring ‘08
Teratogens
- substances that may cause structural
and/or functional fetal abnormalities
(dose dependent)
Biology of Toxins Final Presentation
Spring ‘08
Teratogens
Introduction
Social and Behavioral Teratogens
Alvena Largo
Psychoactive Drugs and Diseases
Candice Lovato
Environmental Toxins and Fetal Development
Jennifer Rice
Teratogens: Medications
Katie Weeks
Introduction
• Critical periods during Fetal Development
www.cerebralpalsychildren.com/CP1.jpg
Introduction
• Teratogens vary from recreational and
medicinal drugs to behavior and
environmental factors. The devastating
effects of many teratogens depends on
gestational timing and duration of exposure.
• The following presentation reveals some of
the most common and hazardous teratogens.
Social and Behavioral Teratogens
• Alvena Largo
news.bbc.co.uk
Social and Behavioral Teratogens
• Stress
• Diet
• Caffeine
news.bbc.co.uk
wpclipart.com
Stress
• Leads to many problems for mother and fetus.
• Pre-term births and low birth rate are some
dangers for the fetus (March of Dimes).
posetech.com/training/images/treadmillrunning.jpg
Reducing Stress
• Follow good healthy habits such as a good diet and
getting plenty of rest (Organization of Teratology).
• Excess of stress can also lead to bed rest as well as
taking other medications.
• Exercise is a Taboo when pregnant, however it can
increase blood flow to the baby which is good.
• Do not proceed with exercise if pain occurs and
sustain from exercising baby area.
Foods to stay away from!!!
Its important to watch what you eat when
pregnant because some food may contain
Listeria Bacteria
• Seafood- Source of Omega 3fatty acids,
but contains Mercury and other bacteria
• Deli Meats- may cause food-borne
illnesses
• Dairy Products- potentially causes illness
if not using pasteurized products (Harms,
Roger W. M.D., et al)
fishfloridakeys.com/stonecrab.htm
Other things to prevent sickness
while pregnant:
• Wash hands, clothes as necessary
• Cook all food well!!
• Avoid ALL raw foods!!
www.nbutexas.com/Images/washing_machine.png
Caffeine
• Caffeine is a stimulant found in many foods, beverages
and plants (naturally).
• Increases alertness within 1 hour and lasts up to 6 hours.
• Although increased consumption doesn’t cause birth
defects, its important to remember that caffeine will cross
the placenta and can affect the fetus (Cnattingius S, et al)
• Some studies have shown than in combination with
alcohol or smoking may cause miscarriages.
• Women should also be aware that caffeine can also be
passed through breast milk (Organization of Teratology).
Psychoactive Drugs
• Candice Lovato
www.azag.gov
Psychoactive Drugs
• Among women of reproductive age (15-44)
– 90% have used alcohol
– 44% have used marijuana
– 14% have used cocaine
(Rayburn, 2007)
Psychoactive Drugs
Most women abstain or decrease substance use once
their pregnancy is medically diagnosed. However,
diagnosis may take as long as one to several months
post conception. The first three months of pregnancy
are crucial for fetal development. Therefore, substance
use during this time may be detrimental to the fetus.
www.fshtest.com/fhc-114.jpg
Psychoactive Drugs
• Alcohol is one of the most common causes
of birth defects in the U.S. and therefore
one of the most researched. (Gundogan et al., 2007)
www.cap.org.uk/.../0/bottles2_300_afoncn.jpg
Psychoactive Drugs
• Some of the clinical features of Fetal Alcohol Syndrome
are:
– Growth deficiency (pre and postnatal)
– Abnormal facial features (small eyes, sunken nasal bridge, smooth
skin surface between nose and upper lip, etc)
– Central Nervous System dysfunction
(Fryer et al., 2007)
– Defects in brain morphology (attributed to abnormal cell growth,
differentiation and migration)
(Cuzon et al., 2008)
Psychoactive Drugs
files.turbosquid.com
Fetal nicotine exposure
increased risk for : spontaneous abortion, limb
malformation, defects in lung and urinary tract
development. (Berger, 2006)
Fetal marijuana exposure
increased risk for: defects in Central Nervous
System, delayed fetal growth. (Berger, 2006)
byrumjason.files.wordpress.com
Psychoactive Drugs
• Fetal cocaine exposure
increased risk for: premature labor, delayed fetal
growth, fetal death, symmetric growth restrictions
and childhood learning disabilities.
www.brake.org.uk/resources/images/Cocaine.jpg
Diseases
•Candice Lovato
www.lurican-pictures.co.uk/.../rubella.PNG
Diseases
•
If a woman has certain diseases while
pregnant, it may harm the fetus during
the gestational period or during delivery.
•
It is therefore very important to maintain
good health during pregnancy as well as
attend regular medical appointments.
Diseases
• Rubella: An acute, contagious viral
infection.
In the three trimesters of pregnancy, the
embryo is more vulnerable to the virus. It
may cause blindness and deafness. It may
also cause brain damage. (Berger, 2006 and
http://www.healthscout.com)
Diseases
• Toxoplasmosis: An infection caused by a
parasite, remains in the host for life.
If a pregnant women is infected, her baby
will be born with the disease. It may cause
blindness, deafness, cerebral palsy, brain
damage and mental retardation.
(Berger, 2006 and http://www.medicinenet.com)
Diseases
• Syphilis: a sexually transmitted bacterial
infection.
A child may contract the infection during
birth or during pregnancy. May cause
damage to the brain, bone and may even
lead to death.
(Berger, 2006 and http://www.pregnancy-info.net)
Diseases
• Infections of the gums, teeth and urinary
tract: non-specific infection
Minor infections may lead to premature
birth, which may have several adverse
effects on the child.
(Berger, 2006)
Links to Information on Fetal
Development
•
http://channel.nationalgeographic.com/episode/in-the-womb-2228/#tabVideos/01586_05
•
http://health.discovery.com/centers/pregnancy/americanbaby/fetaldevelopm
ent.html
•
www.babycenter.com
Work Cited
•
CuzonV., Yeh,P. Yanagawa,Y., Obata,K., and Yeh,H. 2008. Ethanol
consumption during Early Pregnancy Alters the Disposition of Tangentially
Migrating GABAergic Interneurons in the Fetal Cortex. Journal of
Neuroscience 28: 1854-1864.
•
Fryer,S., McGee,C., Matt,G., Riley,E. and N,S. 2007. Evaluation of
Psychopathological Conditions in Children With Heavy Prenatal Alcohol
Exposure. Pediatrics 119: 733-741.
•
Gundogan,F., Elwood,G., Longato,L., Tong,M., Feijoo,A., Carlson,R.,
Wands,J. and de la Monte,S. 2007. Impaired Placentation in Fetal Alcohol
Syndrome. Plancenta 29: 148-157.
•
Rayburn,W. 2007. Maternal and Fetal Effects from Substance Use. Clinics in
Perinatology 34: 559-571.
•
Berger,K.S. 2006. The Developing Person. NY: Worth Publishers
•
http://www.medicinenet.com
Work Cited
•
http://www.healthscout.com
Environmental Toxins and
Fetal Development
Jennifer Rice
Environmental Toxins

Environmental toxins can enter the body
of a pregnant woman in several ways:



Drinking Water
Contamination from
Food Packaging
Air Pollutants
www.allposters.com
Methods of Investigation

We have increasing
knowledge about the
effects of environmental
toxins, from research using:


Animal Models
Human longitudinal and
epidemiological studies
Toxins in our water: TCE & TCA

TCE is an industrial chemical


In its manufacture, use, and
disposal, groundwater can
become contaminated
TCA is a TCE metabolite

Water treatment with
chlorine produces TCA
Toxins in our water: TCE & TCA


Gestational exposure to TCE and TCA has
been linked with increased risk of
congenial heart defects in humans
The EPA recommended safe limit for
human exposure is
5ppb (parts per billion)
pubs.rsc.org
Toxins in our water: TCE & TCA

Chicken embryos


Chicken embryos were given TCE and TCA
levels near the EPA limit for humans
Exposure during late cardiac development
lead to heart malformation and dysfunction
Toxins in our Food

Bisphenol A is an estrogenic compound
used as monomer to manufacture:


Polycarbonate plastic
The resin used to line most food and drink
cans
Polycarbonate and Bisphenol A

www.dwell.com
www.backcountrygear.com

Ester bonds in polycarbonate
are easily hydrolyzed by high
temperatures or high/low pH
Human fetuses, at birth,
have 2-3 ng/ml biologically
active bisphenol A in
their bodies
Polycarbonate and Bisphenol A

Mice



Exposed during pregnancy to levels of
bisphenol A lower than average human levels
Male offspring have malformation and
enlargement of prostate
In humans a similar effect is likely to increase
rates of prostate cancer later in life
Toxins in our Air


There is a wide variety of air pollutants
distributed throughout the world
Sources of toxins:




Vehicles burning diesel and gasoline
Power plants burning coal
Burning of wood for
heat and cooking
Industrial incineration
of waste
www.abc.net.au
Toxins in our Air

Some of the most dangerous air pollutants
are Polycyclic Aromatic Hydrocarbons
(PAH)


They are known carcinogens and mutagens in
humans
TCDD (Dioxin) is one of the most harmful
www.spitzer.caltech.edu
Toxins in our Air

In Great Brittan


Children born near “hot spots” of toxin
emissions showed at much higher risk of
childhood cancers
Most of the 22,458 cases of childhood
cancer and leukemia studied
could be traced back to
atmospheric contaminants.
Polycyclic Aromatic Hydrocarbons

In Krakow, Poland and New York City


Increased exposure to PAH, even at low
levels, leads to reduction in birth weight
Low birth weight and early delivery have
been associated with
developmental and
health problems as the
child grows.
www.uwm.edu
Focus on a dangerous toxin: TCDD

2,3,7,8-tetrachlorodibenzo-p-dioxin


Known as Dioxin, or TCDD
Persists in the environment a long time,
and has a long half-life in humans
www.chm.bris.ac.uk
TCDD in human tissues


Most people have ~2-5 ppt (parts per
trillion) in their bodies, even without an
obvious exposure source
Dioxin compounds tend to accumulate in
adipose tissue

Women have more adipose tissue, so higher
concentrations of TCDD than men
Fetal exposure to TCDD


www.dgfett.de

Toxins that are lipid-soluble tend to cross
through the placenta by simple diffusion
Dioxin is also transferred through breast
milk, which can carry lipid-soluble
compounds
These lead to higher
concentrations of TCDD
in the fetus and newborn
than in the mother
TCDD and Thyroid Function

TCDD has a similar structure to thyroid
hormones

Dioxin
www.ktf-split.hr
Thyroid
www.answers.com

TCDD competes with normal thyroid hormones,
leading to symptoms of hypo-thyroidism
Exposure from placental transfer
and breast milk may lead to
thyroid dysfunction in infants
TCDD and Immune Function

Fetal exposure to TCDD has been linked to
impaired function in:




Cytotoxic T-cell response
Delayed-type
hypersensitivity
Graft vs. host response
Thymus and bone-marrow
function
Resistance to bacteria and bacterial toxins
www.karlloren.com

TCDD and Immune Function



Mice were exposed to prenatal doses of TCDD
similar to normal human exposure
Adult offspring were exposed to Influenza A
Immune impairment was dose- and sexdependent


Higher exposure lead to greater immune system
impairment
In male offspring, only the
innate response was impaired,
while in females, both innate
and adaptive responses were
affected
www.molvray.com
TCDD Mechanism of Action


The Aryl hydrocarbon Receptor (AhR) is a
ligand-activated transcription factor
TCDD acts as a ligand for AhR in the
cytosol


When it binds AhR, an inhibitor protein leaves
AhR moves to the nucleus and binds Dioxinresponse elements (DREs) in 5’ region of
target genes
TCDD Mechanism of Action

Exposure to TCDD leads to
upregulation of



www.cbp.pitt.edu

CYP1A1 and CYP1B1
Other drug-metabolizing
enzymes
Genes that regulate the
cell cycle
Inflammatory mediators
Environmental Toxins

We have looked at the effects of:




TCE and TCA in drinking water  congenital
heart defects
Bisphenol A  prostate malformation and
enlargement
Air pollutants 
childhood cancers
and leukemia
PAH  low birth
weight and early
delivery
www.thetripflare.org
Environmental Toxins

TCDD/Dioxin
 concentration
in fetus through placenta and breast milk
 thyroid dysfunction
 Impaired immune response
 Disruption of gene expression
www.measurement.gov.au
Multiple Exposures

Each of these toxins individually can cause
problems in fetal development


Typically, humans are exposed to multiple toxins
which can interact with each other, compounding the
effects
Many of the toxins cause primary health effects,
as well as secondary, lesser effects

Secondary effects can multiply with one another into
dangerous problems
How to protect yourself and others



Personally avoiding dangerous toxins
Education of at-risk populations
Reducing your personal impact


Burning fewer
fossil fuels
Encouraging companies
to implement practices
that reduce our exposure to toxins
in our water, food supply, and air
Resources








Choi, H., et al. International Studies of Prenatal Exposure to Polycyclic
Aromatic Hydrocarbons and Fetal Growth. Environmental Health Perspectives,
2006. 114,11: 1744-1750.
De Rosa, C.T., et al. A Regional Approach to Assess the Impact of Living in a
chemical World. Annals of the New York Academy of Sciences, 2006. 1076:
829-838.
Drake, V.J., et al. Cardiogenic Effects of Trichloroethylene and Trichloroacetic
Acid Following Exposure during Heart Specification of Avian Development.
Toxicological Sciences, 2006. 94,1: 153-162.
Giacomini, S.M., et al. Dioxin Effects on neonatal and infant thyroid function:
routes of perinatal exposure, mechanisms of action and evidence from
epidemiology studies. International Archives of Occupational and
Environmental Health, 2006. 79: 396-404.
Knox, E.G., et al. Childhood cancers and atmospheric carcinogens. Journal of
Epidemiology and Community Health, 2005. 59: 101-105.
Timms, B.G., et al. Estrogenic chemicals in plastic and oral contraceptives
disrupt development of the fetal mouse prostate and urethra. PNAS, May 10,
2005. 102,19: 7014-7019.
Williamson, M.A., et al. Aryl Hydrocarbon Receptor Expression and Activity in
Cerebellar Granule Neuroblasts: Implications for Development and Dioxin
Neurotoxicity. Toxicological Sciences, 2005. 83,2: 340-348.
Vorderstrasse, B.A., et al. A dose-response study of the effects of prenatal and
lactational exposure to TCDD on the immune response to influenza virus.
Journal of Toxicology and Environmental Health, 2006. 69: 445-463.
Teratogens: Medications
Katie Weeks
Introduction:

In addition to
recreational drugs,
alcohol, the
environment, and
diseases, prescribed
and over the counter
medications can
disrupt the
development of the
fetus.
Introduction:


A study showed that
45% of women take at
least one prescription
drug and many more
take over the counter
drugs.
A British study also
suggested that only 10%
of women take
medications during
early pregnancy.
Introduction:
Approximately 1 to 3% of the general
population has major congenital defects
at birth.
 Of these, only 2 to 3% are thought to be
due to drug treatment.
 Currently, few drugs are proven
teratogens, but they are important to
study, for they are preventable.

Drug Metabolism During
Pregnancy:



Due to physiological changes during pregnancy, it
is important to give extra precaution to the drugs
used and the doses taken.
The metabolism and elimination of drugs varies
greatly during pregnancy.
“Clearance rates of many drugs increase during
late pregnancy due to increases in both hepatic
and renal elimination processes (e.g., digoxin,
phenytoin), while in some cases clearance rates
decrease (e.g., theophylline).”
Sensitive Periods for Teratogens:


The effect of a teratogen depends on the time of
development in which the fetus is exposed to that
teratogen.
Pre-implantation exposure:
– “All or none” Period= Insults to the embryo may result in
death.
– However, the embryo still contains totipotent cells which
may allow for repair from damage.
– Teratogens during this time will most likely not result in
congenital malformations.
Sensitive Periods for
Teratogens:

Embryonic Period of Development:
– 18 to 54-60 days after conception.
– Organogenesis occurs during this time.
– Maximum sensitivity to teratogenic effects.
• Tissues are differentiating rapidly and they will no
longer be able to repair damaged cells.
– Teratogenic exposure during this time has the greatest
chance of causing a structural defect.
– The organ that is effected depends on the specific organ
system that is developing during the specific time of
exposure to the teratogen.
Sensitive Periods for
Teratogens:

Fetal Stage of Development:
– The end of the embryonic stage until birth.
– Growth and maturation of already formed organs
occurs.
– Teratogenic exposure during this time will effect
the growth of the fetus:
• The size of an organ/fetus
• The function of an organ
• Termed “Fetal toxicity”
Sensitive Periods for Teratogens:
If a teratogen is going to effect the
closing of the neural tube, for example,
it must be consumed in the first 3.5 to
4.5 weeks of pregnancy.
 There are some organs that are sensitive
to teratogens for the entirety of the
pregnancy, including the central
nervous system.

Links to learn about Fetal Development
Month by Month:



http://channel.nationalgeographic.com/episode/in-the-womb-2228/#tabVideos/01586_05
http://health.discovery.com/centers/pregnancy/americanbaby/fetaldevelopment.html
www.babycenter.com
Common Concerns… Tylenol



It is shown that taking the recommended doses of
acetaminophen (Tylenol) during pregnancy cannot cause a
miscarriage.
A thorough study showed that acetaminophen cannot effect the
developing brain of the baby (Studied IQ to age 4)
Taking too much acetaminophen can cause kidney and liver
damage and anemia in the mother, and can have similar effects
in the baby.
– Safe dose is less that 4000mg/day of acetaminophen.

Only a small amount of acetaminophen gets into the breast milk
and is considered safe to take while breast feeding as well.
Ibuprofen…





Ibuprofen used in early pregnancy has been shown by some studies to
increase the risk of miscarriage, but other studies contradict this.
There are concerns that drugs such as ibuprofen may cause problems
with the implantation of the embryo.
There is no definite risk, but women who wish to become pregnant,
may want to stay away from ibuprofen.
Not Shown to cause birth defects if used during the first two trimesters.
The Concern:
– Ibuprofen use during the third trimester is suggested to cause the
ductus arteriosus (a part of the fetal heart) to close prematurely.
• May cause high blood pressure in the fetal lungs.
• Use late in pregnancy may inhibit labor or reduce the amount of
amniotic fluid
Tetracycline…




Antibiotic used to treat acne and
some respiratory conditions.
No birth defects shown in
children who were exposed
during the first trimester.
If taken after the fourth month,
there is a risk of causing
discoloration of the baby’s teeth.
Suggested to affect the
calcification of the bones and
teeth and the growth of some
bones.
Echinacea…


Only one study done suggests
there is not an increased risk of
birth defects or miscarriage with
echinacea use.
Taking an excessive amount of
this alcohol containing product
may cause birth defects.
Chemotherapy:



Risk for birth defects if
chemotherapy is undergone
during the first trimester of
pregnancy.
May increase the risk of
miscarriage.
Chemotherapy during the
second and third trimesters
pose a less severe risk.
– Most of the organs (except
the brain and reproductive
system) are fully developed
by this time.
Antidepressants:



Prozac.
– No sign of it causing major birth defects.
– There is suggestion that minor birth defects (not medically
significant) may occur if taken during the first trimester of
pregnancy.
Zoloft
– Not shown to increase the chance of birth defects more than 3 to 5
% more than the general public.
– Much more research needed.
Paxil
– One study by the manufacturers suggested that use during the first
trimester may increase the risk of having a baby with a heart defect.
Depo Provera (Birth Control Shot):

Suggested that the use of the shot may cause
some malformations in the genitalia of the
baby.
 One study suggested that use during the first
trimester may lead to an increased risk of
polysyndactyly and chromosomal
abnormalities.
 Possibly causes lower birth weight.
 More research needed.
Vaccines:



Varicella (Chicken Pox)
– No major malformations suggested
– Wait one month after vaccine to become pregnant.
Influenza Vaccine
– Considered safe for use during pregnancy.
MMR Vaccine
– No increased risk of birth defects suggested
– Wait 28 days after vaccine to become pregnant.
Proven Human Teratogens:
Proven to cause major birth defects…















Alcohol
Angiotensin converting enzyme inhibitors (ACEI) (captopril, enalapril,
lisinopril)
Carbamazepine
Cocaine
Coumarin anticoagulants
Diethylstilbestrol
Folic acid antagonists: Aminopterin and methotrexate
Hydantoins (phenytoin and trimethadione)
Isotretinoin (13-cis-retinoic acid)
Lithium
Misoprostol
Tetracyclines
Thalidomide
Valproate
For details on each of these drugs, go to http://www.nvpvolumes.org/p2_4.htm
Possible Teratogenic Drugs:

D-penicillamine–

Methimazole–

High doses are
associated with
connective tissue
disorders.
Thought to be
associated with scalp
defects.
Diazepam– During first trimester
exposure, there
seems to be a slight
increase in the
incidence of cleft
palate and lip.
References:

http://otispregnancy.org/otis_fact_sheets.asp

http://www.nvp-volumes.org/p2_4.htm

http://www.chw.org/display/PPF/DocID/22924/
router.asp

http://msds.chem.ox.ac.uk/teratogens.html