Thyroid Hormone, Brain Development and the Environment

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Thyroid Hormone, Brain Development and the
Environment

• R. Thomas Zoeller
• University of Massachusetts-Amherst

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Thyroid Disease is common

• Over 10 of people had abnormal thyroid hormone
  levels (and didnt know it). 40 of people being
  treated for thyroid disease had abnormal levels.

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Thyroid Disease
Our best estimates of the incidence of
hypothyroidism is 350/100 000/year in women and
80/100 000/year in men the incidence of
hyperthyroidism is 80/100 000/year in women and
8/100 000/year in men.
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Thyroid Hormone is Essential for Normal Brain
Development
The critical period of thyroid hormone action
in brain development was defined as that period
after birth when TH therapy must be initiated to
rescue the infant from cretinism. Brown AW et al.
(1939) Hypothyroidism and cretinism in childhood.
VI. Influence of thyroid therapy on mental
growth. Amer J Dis Child 57517-523.
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Thyroid Disease
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Thyroid Disease
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Congenital Hypothyroidism
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Congenital Hypothyroidism
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Congenital Hypothyroidism
Negative consequences in terms of HRQoL,
development, and self esteem are prevalent in
young adults with CH. Health care physicians
should be attentive to these consequences and
provide additional support (emotional and
educations guidance) if necessary. J Clin
Endocrinol Metab 932654 2008
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Why is it so confusing??
Perchlorate
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What is Perchlorate?

• Can occur naturally
• Manufactured largely as a component in solid
  propellants.
• Was/is used medically to treat and evaluate
  thyroid function.

Perchlorate
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Locations of reported environmental releases of
perchlorate into ground water
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Perchlorate blocks Radioactive Iodide Uptake
(RUI)
Thyroid glands take up iodine and this is used
medically to diagnose thyroid disease
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Whats all the Fuss?

• California EPA set a drinking water standard of 6
  ppb
• Massachusetts DEP set a graded standard from 1 to
  6 ppb
• U.S. EPA recommended a standard of 24.5 ppb
• The perchlorate study group argues that 200 ppb
  is safe.
• The National Academy of Sciences (NAS)
  recommended a reference dose of 0.007 mg/kg
• Some consultants to the perchlorate industry have
  argued that 1,400 ppb is safe according to the
  National Academy of Sciences

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Does perchlorate cause harm?

• To cause harm
• People would have to be exposed to levels
  sufficient to cause a reduction in serum thyroid
  hormone levels and at a time during the life
  cycle that a reduction in TH would cause harm

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Perchlorate Exposure
Most human milk samples contained
perchlorate. All human urine samples contained
perchlorate.
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Science behind the Risk Analysis for Perchlorate

• Human Studies
• Clinical Reports
• Occupational
• Adult Volunteers
• Epidemiological Studies
• Newborns
• Children

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Science behind the Risk Analysis for Perchlorate

• Animal Studies
• 90-day study in rats (hormone levels)/Thyroid
  histopath.
• Neurobehavioral studies in rats
• Developmental neurotoxicity study
• Immunotoxicity
• Genotoxicity

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Greer Data
Found that the No Effect Level was 5.2 µg/kg
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Perchlorate and Thyroid Function
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If perchlorate affects thyroid function in adult
women, what about infants?

• Newborns have no stored thyroid hormone
• Newborns clear thyroid hormone faster
• Infants are sensitive to small reductions in TH
• There are permanent effects of TH insufficiency
  in infants

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The continuing saga.
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Why is the science so fuzzy?

• Why isnt there more certainty

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Thyroid Hormones in Individuals

• Individuals appear to have their own set-point
  for serum T4 and TSH
• Andersen et al. (2002) Narrow individual
  variations in serum T(4) and T(3) in normal
  subjects a clue to the understanding of
  subclinical thyroid disease. J Clin Endocrinol
  Metab 871068-1072.

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Set-Point is Genetic

• Serum TSH and fT4 varies around a mean that is
  highly correlated in monozygotic twins but not in
  dizygotic twins.

Hansen et al., 2004. JCEM 891181.
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Bottom Line

• Thyroid hormone is essential for brain
  development and health
• Our ability to identify and manage thyroid
  disease may not be as simple as previously
  thought
• Widespread contamination of chemicals like
  perchlorate may be impacting public health in
  significant ways.

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Polychlorinated Biphenyls
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Polychlorinated Biphenyls
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Polychlorinated Biphenyls
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Polychlorinated Biphenyls
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Polychlorinated Biphenyls
PCB 77 is co-planar
PCB 95 is non coplanar
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• PCBs cause a reduction in serum thyroid hormones
  in rodents

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PCBs appear to activate the thyroid hormone
receptor in the developing brain
RC3 mRNA in Dentate Gyrus (Density)
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Cx
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DG
RC3
40
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30
25
0 mg/kg
1 mg/kg
4 mg/kg
8 mg/kg
Pseudocolor image of Autoradiogram following in
situ hybridization for RC3 mRNA
A1254 Dose
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PCBs appear to be metabolized in some tissues to
form compounds that activate the thyroid hormone
receptor
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Bisphenol A

• Component of plastic
• Polycarbonates
• Dental sealants
• Can linings

Tom Wiese
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Moriyama et al., JCEM 2002 87(11)5185.
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BPA antagonizes TR-? mediated negative feedback
in vivo
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Elevated levels of TH increase RC3/Neurogranin
expression on P15

• BPA may be a TR? selective antagonist.

Endocrinology 146(2) 607-612
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Polybrominated Diphenyl Ethers
PBDEs are found in human tissues in the US at 10x
the level found in Europe. Very high levels in
house pets (infants/children?)
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Polybrominated Diphenyl Ethers
Marsh, Bergman et al., 1998, Organohalogen
Compounds 37305.
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Triclosan
Triclosan is a bacteriocidal agent found in
soaps, toothpaste, etc.
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Conclusions

• Thyroid hormone is essential for normal brain
  development and for health.
• Many environmental factors are known to affect
  the thyroid system at many levels
• There are likely to be genetic predispositions to
  be sensitive to environmental factors
• With increasing incidence of thyroid disease, we
  cannot ignore the environmental link

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Acknowledgements
Collaborators Mary Gilbert, Duncan Ferguson,
Kevin Crofton, Mike DeVito, Jeff Fisher, Carole
Yauk (HC), Mike Wade (HC)