Thyroid Disease

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Thyroid Hormone, Brain Development and the Environment : 

Thyroid Hormone, Brain Development and the Environment R. Thomas Zoeller University of Massachusetts-Amherst

Thyroid Disease is common : 

Thyroid Disease is common Over 10% of people had abnormal thyroid hormone levels (and didn’t know it). 40% of people being treated for thyroid disease had abnormal levels.

Thyroid Disease : 

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.

Thyroid Hormone is Essential for Normal Brain Development : 

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 57:517-523.

Thyroid Disease : 

Thyroid Disease

Thyroid Disease : 

Thyroid Disease

Congenital Hypothyroidism : 

Congenital Hypothyroidism

Congenital Hypothyroidism : 

Congenital Hypothyroidism

Congenital Hypothyroidism : 

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 93:2654 2008

Slide 12: 

Perchlorate Why is it so confusing??

What is Perchlorate? : 

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

Locations of reported environmental releases of perchlorate into ground water : 

Locations of reported environmental releases of perchlorate into ground water

Perchlorate blocks “Radioactive Iodide Uptake” (RUI) : 

Perchlorate blocks “Radioactive Iodide Uptake” (RUI) Thyroid glands take up iodine and this is used medically to diagnose thyroid disease

What’s all the Fuss? : 

What’s 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

Does perchlorate cause harm? : 

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

Perchlorate Exposure : 

Perchlorate Exposure Most human milk samples contained perchlorate. All human urine samples contained perchlorate.

Science behind the Risk Analysis for Perchlorate : 

Science behind the Risk Analysis for Perchlorate Human Studies Clinical Reports Occupational Adult Volunteers Epidemiological Studies Newborns Children

Science behind the Risk Analysis for Perchlorate : 

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

Greer Data : 

Greer Data Found that the “No Effect Level” was ~5.2 µg/kg

Perchlorate and Thyroid Function : 

Perchlorate and Thyroid Function

If perchlorate affects thyroid function in adult women, what about infants? : 

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

The continuing saga…. : 

The continuing saga….

Why is the science so fuzzy? : 

Why is the science so fuzzy? Why isn’t there more “certainty”

Thyroid Hormones in Individuals : 

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 87:1068-1072.

Set-Point is Genetic : 

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 89:1181.

Bottom Line : 

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.

Slide 29: 

Polychlorinated Biphenyls

Slide 30: 

Polychlorinated Biphenyls

Slide 31: 

Polychlorinated Biphenyls

Slide 32: 

Polychlorinated Biphenyls

Slide 33: 

PCB 77 is “co-planar” Polychlorinated Biphenyls PCB 95 is non coplanar

Slide 34: 

PCBs cause a reduction in serum thyroid hormones in rodents

PCBs appear to activate the thyroid hormone receptor in the developing brain : 

PCBs appear to activate the thyroid hormone receptor in the developing brain 25 30 35 40 45 50 55 60 RC3 mRNA in Dentate Gyrus (Density) * * RC3 Pseudocolor image of Autoradiogram following in situ hybridization for RC3 mRNA Cx DG 0 mg/kg 1 mg/kg 4 mg/kg 8 mg/kg A1254 Dose

Slide 36: 

PCBs appear to be metabolized in some tissues to form compounds that activate the thyroid hormone receptor

Slide 37: 

Bisphenol A Tom Wiese Component of plastic Polycarbonates Dental sealants Can linings

Slide 38: 

Moriyama et al., JCEM 2002 87(11):5185.

Slide 39: 

BPA antagonizes TR- mediated negative feedback in vivo

Slide 40: 

Elevated levels of TH increase RC3/Neurogranin expression on P15 Endocrinology 146(2): 607-612 BPA may be a TR selective antagonist.

Slide 41: 

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?)

Slide 42: 

Polybrominated Diphenyl Ethers Marsh, Bergman et al., 1998, Organohalogen Compounds 37:305.

Slide 43: 

Triclosan Triclosan is a bacteriocidal agent found in soaps, toothpaste, etc.

Conclusions : 

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

Acknowledgements : 

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