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
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
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
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