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TRANSTHYRETIN (TTR): CARRIER OF THYROXINE AND IT’S EVIL TWIN (ENVIRONMENTAL POLLUTANTS)
Wauwatosa West SMART Team: Zaynab Hassan, Madeline Jordan, Leah Rogers, Zoe Stack, Kayla Thao, Cheung Wongtam and Aleksandra Zielonka
Teacher: Mary Haasch Mentor: Joseph McGraw, Ph.D., and Cameron Patterson, School of Pharmacy, Concordia University
ABSTRACT
HYPOPLASTIC LEFT HEART SYNDROME
STRUCTURE OF TRANSTHYRETIN
Transthyretin (TTR) is a carrier protein in the blood that binds to and transports the
thyroid hormone thyroxine throughout the human body. The thyroid hormone is
necessary for fetal development and metabolism regulation. TTR is a tetramer formed
from two dimers. Ala-108, Ser-117, Thr-119, Lys-15, Leu-17, Thr-106, and Val-121 all
play a role in binding the thyroxine in a hydrophobic channel formed where the two
dimers come together. Polybrominated diphenyl ethers (PBDEs), found in flame
retardants, which are in numerous household products, are converted in the body to
hydroxy-PBDEs. Hydroxy-PBDEs mimic the shape of thyroid hormones allowing them to
bind with TTR. Hydroxy-PBDEs can have a stronger affinity to bind to TTR, disrupting the
transport of the thyroid hormone necessary for developmental and metabolic
processes. An initial study shows a possible correlation between high levels of PBDEs
and hypoplastic left-heart syndrome, a condition found in four out of 10,000 newborns
(Lucile Packard Children’s Hospital at Stanford) in which the left side of the heart does
not fully develop. Wauwatosa West SMART Team (Students Modeling A Research Topic)
modeled TTR using 3D printing technology.
•Tetramer from two dimers
•Hydrophobic channel with four binding
sites
•Ala-108, Ser-117, Thr-119, Lys-15, Leu17, Thr-106, and Val-121 play a role in
binding thyroxine
•Arg-378 is one amino acid that controls
binding and release
•Two separate halves of one dimer shown
below
• Left ventricle misshapen and
significantly smaller from birth
• Heart not capable of pumping
blood efficiently through the body
•Condition fatal without treatment
•Cause of hypoplastic left heart
syndrome unknown
Dr. Pelech and Dr. Dellinger studied environmental contaminant serum
concentrations in eight infants diagnosed with hypoplastic left heart
syndrome (HLHS). Based on these results, Dr. Joseph McGraw and his
colleagues are currently investigating a possible correlation between HLHS
and high levels of PBDEs in mother infant pairs.
KEY
•Thyroxine: Dark Purple
•Beta Sheet: Blue
•Amino Acids: Yellow
•Alpha Helix: Green
High levels of PBDEs were found in one mother-infant pair (shown below).
NHANES*
WPCR*
Geo Mean ng/g
95th P'Tile
Mother #2 Child #2
PBDE 47 19.6 (16.4-23.5) 155 (102-239)
166.2
394.1
PBDE99 3.72 (3.15-4.40) 33.3 (23.3-46.0)
34.1
117.0
PBDE153 4.78 (4.20-5.43) 54.5 (34.6-62.9)
38.7
58.8
THYROXINE: THE THYROID HORMONE
1ICT.pdb
TRANSTHYRETIN: THYROXINE CARRIER
PLACENTAL DISK
Fetus
Side
Mother
Side
•Second most prevalent of three thyroxine
carriers
•Binds to thyroxine in blood stream
•Believed primary carrier of thyroxine into brain
•Believed primary carrier of thyroxine through
placenta into fetal circulation
•Proposed that TTR-thyroxine shuttled from
mother to fetus
•Exact mechanism unknown
O2 + Nutrients
TTR-thyroxine complex
CO2 + Waste
Fetal
circulation
Maternal
circulation
•Once in placental circulation, TTR-thyroxine
goes to trophoblasts (early stage placental
cells) and later to fetal circulation.
Acknowledgements: NIEHS Children's Environmental Health Sciences P30 Core Center Pilot Grant
Dr. John Dellinger (Concordia University Wisconsin)
Dr. Andrew Pelech (Children’s Hospital Wisconsin)
Dr. Larry Needham NIEHS National Center for Environmental Health
POLYBROMINATED DIPHENYL ETHERS (PBDEs)
* Average PDBE concentrations from the National Health and Nutrition Examination Survey
compared to data from the Wisconsin Pediatric Cardiac Birth Defect Registry
•Environmental toxins in flame
retardants
•Commonly added to household
products such as furniture,
clothing, electronics, cars, walls
• Exposure due to consumption of
food and respiration
•Levels risen significantly in the
United States over the past two
decades; Milwaukee has high
concentrations
•Once absorbed in the body and
metabolized, stored in lipids,
found in blood, and breast milk
•Metabolites structurally similar to
thyroxine, allow binding to TTR
•Some Hydroxy-PBDE congeners
bind more strongly to TTR than
thyroxine
•Has been shown to disrupt
thyroid hormone transport
throughout the body
•Certain forms have been banned
in Europe since 2004
•PCBs, banned industrial
chemicals, structurally similar to
PDBEs and thyroxine
•PCBs shown to have negative
influence on thyroid function
•Hypothesis: disruption of normal thyroxine transfer into fetal blood
circulation may play a role in hypoplastic left heart syndrome
•Known: elevated or depressed levels of thyroxine in fetal circulation
are detrimental to the development and health of the fetus
•Formation of PDBE-TTR complex before entering fetal circulation may
create a thyroxine deficit
•Formation of PDBE-TTR complex once in fetal circulation may cause
an excess of thyroxine
THYROXINE
HYDROXY-PBDE
CONCLUSION
PCB METABOLITE
Comparison Between Concentrations of PBDEs
in Breast M ilk from North America and Europe
Sam ples collected in
Austin & Denver
200
Concnetration (ng/g lipid weight)
•Plays a part in the development of the brain, skeleton, heart, and other organs
•Hyperthyroidism (too much thyroxine) causes weight loss, diarrhea, racing heart, and
irritability
•Hypothyroidism (too little thyroxine) causes weight gain, sluggishness, slow heart
rate, low body temperature, and low blood pressure
•Deficiencies in thyroid hormone concentrations before birth and shortly after birth
negatively affects the heart rate, growth, hearing, motor control, and intelligence
North America
Sweden
Finland
Sam ples collected in
New Y ork State
150
1004
50
Transthyretin might be a component in causing birth defects, which could
include hypoplastic left heart syndrome (HLHS). As previously stated, one
mother-infant pair showed unusually high levels of PBDEs. This data was
collected from eight mothers and infants with HLHS. More research is
needed to determine if there is a correlation between this heart defect
and PBDE’s. Transthyretin could play a role in this process. PBDEs may
disrupt normal thyroxine circulation by displacing thyroxine in the TTRthyroxine complex. This data is inconclusive and suggests further
investigation.
Canadian
Milk Bank
Canadian
Milk Bank
0
1975
1980
1985
1990
1995
2000
Sampling Year
Canadian Milk Bank and New York State from Ryan and Patry 2000, Denver and Austin results from Papke et al
2001; Swedish data from Meironyte Guvernius and Noren 2001, Finnish data from Strandman et al. 2000
The SMART Team Program (Students Modeling A Research Topic) is funded by a grant from NIH-SEPA 1R25OD010505-01 from NIH-CTSA UL1RR031973.
Leijs, M. et. al. (2012). Tyroid hormone metabolism and environmental chemical exposure. Environmental Health, 11, Retrieved from
http://www.ehjournal.net/content/11/s1/s10
Wilfred M., et. al. (2004). Tyroid hormone receptor alpha is a molecular switch of cardiac function between fetal and postnatal
life. Proceedings National Academy of Sciences, 101(28), 10332-10337. Retrieved
Cao, J. Et. al. (2010). structure based investigation on the binding interaction of hydroxylated polybrominated diphenyl ehters with thyroxin
transport proteins. Toxicology, (277), 20-28.
Marchesini, G. (2008). Biosensor discovery of tyroxine transport disrupting chemicals. Toxicology and Applied Pharmacology, 232, 150-160.
Binbaum, L. S., & Devito, M. (n.d.). Brominated flame retardants: Cause for concern?.
Campbell, N., & Reece, J. (2008). Biology. (8th ed., p. 990, 214). San Francisco : Pearson Benjamin Cummings.
Dellinger JA, Antoniewski S, Lemoine N, Pelech A. (2008). Etiologic or Causal Factors of Congenital Heart Defects: Gene-Environment
Interaction Hypothesis. Heart Matters, Children’s Hospital of Wisconsin. 11(1):1-4.