Aop:42

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AOP Title

Inhibition of Thyroperoxidase and Subsequent Adverse Neurodevelopmental Outcomes in Mammals


Short name: TPO Inhibition and Altered Neurodevelopment

Authors

Kevin M. Crofton, National Center for Computational Toxicology, US EPA, RTP, NC USA <crofton.kevin@epa.gov>

Mary Gilbert, National Health and Environmental Effects Research Laboratory, US EPA, RTP, NC USA <gilbert.mary@epa.gov>

Katie Paul Friedman, National Center for Computational Toxicology, US EPA, RTP, NC USA <paul-friedman.katie@epa.gov>

Barbara Demeneix, UMR MNHN/CNRS 7221 Evolution of Endocrine Regulations, National History Museum, Paris, France <bdem@mnhn.fr>

Mary Sue Marty, Toxicol. Environ. Res. Consult, Dow Chemical Company, Midland, Michigan; <mmarty@dow.com>

R. Thomas Zoeller, Biology Department, University of Massachusetts, Amherst, MA <tzoeller@bio.umass.edu>

Status

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Under development: Do not distribute or cite.

OECD Project 1.10: Xenobiotic Induced Inhibition of Thyroperoxidase and Depressed Thyroid Hormone Synthesis and Subsequent Adverse Neurodevelopmental Outcomes in Mammals.

This AOP was originally started on the Chemical Mode of Action WIKI sponsored by WHO/IPCS and the MOA was originally described and published by Zoeller and Crofton (2005). Thanks to the following contributors whose work on the MOA-WIKI fostered further development on the AOP wiki: Michelle Embry, Richard Judson, Vicki Dellarco, Chihae Yang, Kevin Crofton.

This AOP page was last modified on 12/11/2016.

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Abstract

This AOP describes one adverse outcome that results from the inhibition of thyroperoxidase (TPO) during mammalian development. Chemical inhibition of TPO, the molecular-initiating event (MIE), results in decreased thyroid hormone (TH) synthesis, and subsequent reduction in circulating concentrations of THs. THs are essential for normal human brain development, both prenatally and postnatally, modulating neural proliferation and differentiation, synaptogenesis, and cell migration. Therefore, chemicals that interfere with TH synthesis have the potential to cause TH insufficiency that may result in adverse neurodevelopmental effects in offspring; this AOP focuses solely on the neurodevelopmental effects that may be mediated by TH insufficiency in the hippocampus. The hippocampus is critically involved in cognitive, emotional, and memory function. The adverse consequences of TH insufficiency depend both on severity and developmental timing, indicating that exposure to thyrotoxicants may produce different effects at different developmental windows of exposure. Herein we discuss the implications of developmental TPO inhibition for hippocampal anatomy, function, and ultimately cognitive function. The overall weight of evidence for this AOP is strong. The biochemistry of TPO and its essentiality for TH synthesis is well known across species. Gaps in our understanding include the relationship of TH-dependent gene expression and complexities of brain development. Although quantitative information at all levels of KERs is limited a number of applications of this AOP have been identified.

Summary of the AOP

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Molecular Initiating Event

Molecular Initiating Event Support for Essentiality
Thyroperoxidase, Inhibition Strong

Key Events

Event Support for Essentiality
Thyroid hormone synthesis, Decreased Strong
Thyroxine (T4) in neuronal tissue, Decreased Strong
Thyroxin (T4) in serum, Decreased Strong
Hippocampal gene expression, Altered Moderate
Hippocampal anatomy, Altered Moderate
Hippocampal function, Decreased Moderate

Adverse Outcome

Adverse Outcome
Cognitive Function, Decreased

Relationships Among Key Events and the Adverse Outcome

Event Description Triggers Weight of Evidence Quantitative Understanding
Thyroperoxidase, Inhibition Directly Leads to Thyroid hormone synthesis, Decreased Strong Weak
Thyroxin (T4) in serum, Decreased Directly Leads to Thyroxine (T4) in neuronal tissue, Decreased Moderate Weak
Thyroid hormone synthesis, Decreased Directly Leads to Thyroxin (T4) in serum, Decreased Strong Weak
Thyroxin (T4) in serum, Decreased Indirectly Leads to Cognitive Function, Decreased Strong Moderate
Thyroxine (T4) in neuronal tissue, Decreased Directly Leads to Hippocampal gene expression, Altered Moderate Weak
Hippocampal gene expression, Altered Directly Leads to Hippocampal anatomy, Altered Moderate Weak
Hippocampal anatomy, Altered Directly Leads to Hippocampal function, Decreased Moderate Weak
Hippocampal function, Decreased Directly Leads to Cognitive Function, Decreased Moderate Weak
Thyroperoxidase, Inhibition Indirectly Leads to Thyroxin (T4) in serum, Decreased Strong Weak

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Life Stage Applicability

Life Stage Evidence Links
Foetal Strong
Perinatal Strong

Taxonomic Applicability

Name Scientific Name Evidence Links
Rattus sp. Rattus sp. Very Strong NCBI
Homo sapiens Homo sapiens Very Strong NCBI

Sex Applicability

Sex Evidence Links
Male Strong
Female Strong

Graphical Representation

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Overall Assessment of the AOP

Weight of Evidence Summary

Summary Table

Biological plausibility of each of the KERs: HIGH

  • The biochemistry of TPO and its essentiality for TH synthesis is well known across species, with the evidence across vertebrate species, including amphibians, birds, rodents, pigs, and humans.
  • Though serum and brain TH concentrations appear correlated, the amount of qualitative and quantitative data supporting this relationship is more limited. However, there is very strong indirect linkage between serum TH concentrations and abnormal anatomical development in the brain, and subsequent changes in neurophysiological function. In particular, decreased serum THs have been linked with decreased axonal development and synaptic plasticity, leading to decrements in hippocampal-dependent learning and memory functions (Gilbert et al., 2015; Wei et al., 2013; Shiraki et al., 2012).
  • Lastly, the biological plausibility that changes in brain structure and physiology, and specifically aberrations in the hippocampus, lead to abnormal cognitive function is well accepted. TH deprivation during neurodevelopment results in irreversible changes in cognitive function and motor coordination in humans and rats, with the severity of this adverse outcome related to duration, developmental timing, and degree of TH decrease. The most severe phenotype presents as neurological cretinism, but less severe effects on cognitive function have been documented in rodent models, clinical studies, and epidemiological investigations. The adverse neurological outcomes in children suffering from developmental TH disruption are characterized as persistent decreases in behavioral function (Kooistra et al.,2006), delays in psychomotor development (Pop et al., 1999; Pop et al., 2003), decreases in motor coordination and socialization (Berbel et al., 2009), language delays (Henrichs et al., 2010), memory impairments (Willoughby et al., 2014; Wheeler et al., 2011; 2012), and IQ decrements (Willoughby et al., 2014; Wheeler et al., 2011; 2012; Haddow et al., 1999; Henrichs et al., 2010). Rat models of maternal T4 insufficiency have related similar cognitive abnormalities to changes in cytoarchitecture, synaptic regulation, myelination, and neuronal gene expression (Gilbert, 2011; Gilbert et al., 2014; Auso et al., 2004; Royland et al., 2008a; Morte et al., 2010; Bernal, 2007). Due to the complexity of the brain, developmental TH insufficiency affects multiple brain regions; as such, decreased memory, learning, and IQ are cognitive functions impacted by specific gene expression, cytoarchitecture, and anatomical changes in the hippocampus.

Extent of Empirical Support for each of the KERs and the Overall AOP

  • There is overwhelming evidence that supports the concordance between TPO inhibition and alterations in downstream KEs, including alterations in serum and tissue thyroid hormone (TH) concentrations. In rodent models, anti-hyperthyroidism drugs MMI and PTU known to inhibit TPO are used as positive control chemicals for inducing hypothyroxinemia and/or hypothyroidism. Information on the adverse neurodevelopmental outcomes in children often only link maternal serum TH levels with cognitive performance in children, rather than connecting back to the MIE(s) relevant to the serum TH decrease. While a majority of the dose-response data for chemical-induced TPO inhibition, downstream key events, and adverse effects on cognitive function are derived from rodent studies, supportive data from human tissues, epidemiology, and a number of other non-mammalian species (e.g., amphibians, birds) are available.
  • There is considerable indirect evidence that supports a relationship between the degree of serum TH decrease and the severity of adverse impacts on the developing brain in humans and rodents. There is also a good correlation between serum T4 concentrations in neonatal rats and sensory hearing loss. Many rodent studies have used high doses of MMI and PTU to induce perinatal hypothyroidism, whereas fewer studies have used moderate doses in order to decrease T4 only (hypothyroxinemia). There appears to be an indirect, quantitative relationship between serum TH and effects on cognitive function, but more quantitative evidence would be helpful. Systemic treatment of pregnant dams that have received MMI with T4 is known to attenuate subsequent downstream effects on fetal brain triiodothyronine (T3) concentrations (Morreale de Escobar et al., 1988), indicating clear support for the relationship between serum T4 in dams and fetal brain TH concentrations.
  • The majority of the data in support of temporal concordance comes from life-stage specific studies. There are data from perinatal, prenatal-only and postnatal-only exposures that correlate the type of adverse cognitive outcome with the timing of the brain region that controls the behavior including, neuroanatomical, neurophysiological, and neurobehavioral outcomes.

Assess Degree of Quantitative Understanding for Each KER While there is no doubt that alterations in the KEs leads to the KERs responsible for altered cognition, with the exception of data from dose-response studies showing increasing impact with increasing dose for all of the KEs, and KERs, there are very few data sets that allow for quantitative understanding of the KERs and how they relate the MIE to the AO in a quantitative manner.

Uncertainties Current gaps in dose-response relationships include:

  1. a lack of quantitative information regarding the amount of TPO inhibition required to elicit specific decrements in circulating T4 concentrations;
  2. a lack of data to quantitatively associate serum TH concentrations with thyroid hormone concentrations in specific brain regions;
  3. a lack of understanding regarding whether observed changes in TH-responsive gene expression in the hippocampus are causally linked to production of measured changes in hippocampal anatomy, function, and adverse cognitive effects; and,
  4. current inability to quantitatively link TH-responsive gene expression changes in the hippocampus with changes in hippocampal anatomy and function.

Essentiality of the Key Events

Molecular Initiating Event Summary, Key Event Summary

It is widely accepted that each of the key events is essential.

  • Molecular Initiating Event Summary: The molecular initiating event, i.e. inhibition of TPO, is the essential event to initiate this AOP, as supported by in vitro and in vivo evidence. A number of studies have demonstrated that cessation of exposure is known to result in a return to normal levels of thyroid hormone (TH) synthesis and circulatory hormone levels (Cooper et al., 1983). A number of in vivo and in vitro studies consistently demonstrate enzyme inhibition with similar chemicals.
  • Decreased Serum Thyroxine (T4): As described above, and in the Key Event and Key Event Relationships, inhibition of TPO is known to lead to decreased TH synthesis in the thyroid gland, which results in decreased serum T4 concentration.
  • Decreased neuronal tissue T4 concentration: This key event suggests that the available pool of T4 in the brain available for local conversion to T3 for genomic (and non-genomic), thyroid receptor-based actions is reduced following reduction of circulating T4 concentrations. Though many whole animal studies use serum T4 concentrations as a surrogate for understanding availability of T4 to the brain, a few studies have measured brain concentrations of T4, and further in vitro studies have demonstrated the key role for T4/T3 availability to promote thyroid receptor-mediated oligodendrite formation/neurogenesis.
  • Hippocampal Gene Expression, Altered: Less is known about the impact of hormone replacement on TH-responsive gene expression and the qualitative and quantitative relationships between altered TH-dependent gene expression in this brain region and altered hippocampal cytoarchitectural anatomy. It is known that graded doses of TPO inhibitors will produce similar gradations in the number of genes changed and the magnitude of the induced change (Royland et al., 2008a and b).
  • Hippocampal anatomy, altered: Less is known about the impact of hormone replacement on attenuating altered neuroanatomy, as a means of demonstrating essentiality, but it is known that increasing doses of TPO inhibitors or increasing severity of iodine deficiency will increase the degree of anatomical change. Rats exposed developmentally to propylthiouracil (PTU) or developmentally iodine deficient rats demonstrate aberrant brain growth and cytoarchitecture, including impacts on neuronal migration, axonal myelination, and oligodendrocyte accumulation (Lavado-Autric et al., 2003; Goodman and Gilbert, 2007).
  • Hippocampal function, altered: Less is known about the impact of hormone replacement on altered hippocampal neurophysiology, though it is known that increasing doses of TPO inhibitors will increase the magnitude and profile of neurophysiological change. Function of the hippocampus can be detected by measuring synaptic function using field potentials or functional neuroimaging; animal studies using field potential measurements in the hippocampus demonstrate that developmental TH insufficiency corresponds to decreased synaptic function.
  • Decreased cognitive function: Hormone replacement studies have demonstrated reduced or blocked alterations in cognition. Indeed, most developed countries check for childhood hypothyroidism at birth in order to immediately begin replacement therapy. This has been shown to alleviate the majority of the adverse impacts of hypothyroidism in congenitally hypothyroid children. The essentiality of the relationship between hormone levels and this adverse outcome is well accepted. Decreased cognitive function specific to the hippocampal region are related to decrements in memory and learning (particularly spatial, temporal, and contextual memory).

Quantitative Considerations

Summary Table

At present, the quantitative understanding of the AOP is insufficient to directly link a measure of chemical potency as an TPO inhibitor to a quantitiative prediction of effect on cognitive function (e.g., IQ in humans, learning deficits in rodents). Empirical information on dose-response relationships for the KEs, currently unavailable, would inform a computational, predictive model for thyroid disruption via TPO inhibition.

Applicability of the AOP

Life Stage Applicability, Taxonomic Applicability, Sex Applicability

Life Stage Applicability

  • This AOP is applicable for developmental life stages where thyroid hormones guide normal development of the brain. there are clear windows of developmental susceptibility and different brain regions show distinct ontogenetic profiles for TH requirements. Distinct phenotypes have been described in both humans and animal models for different periods of TH insufficiency.

Taxonomic Applicability

  • Evidence for this AOP has been gathered primarily from rats and humans. There are supporting data from amphibians and birds for TPO inhibition leading to altered TH profiles.
  • This AOP is relevant to human neurodevelopment, as well as other mammalian species due to the conserved nature of TH synthesis, transport, metabolism and transcriptional activity. There is strong evidence that this same MIE and many key events are similar in amphibians with a known AO of altered metamorphosis. Extrapolation to other taxa is less certain due to lack of empirical data on TPO (or orthologs) inhibition and any subsequent impacts on hippocampal development and function.

Sex Applicability

  • Clearly applicable in both male and female rats and humans. There are not compelling data to suggest sex differences in susceptibility to TH disruption mediated by inhibition of TPO.

Considerations for Potential Applications of the AOP (optional)

  1. This AOP may provide context for interpretation of data derived from Key Events corresponding to an Integrated Approaches and Testing Assessment (IATA) strategy(e.g., US EPA, 2011).
  2. This AOP stimulated recent efforts to develop a high-throughput screening assay to detect potential thyroperoxidase inhibition (Paul et al., 2014) that could inform quantitative structure activity relationships, read-across models, and/or systems biology models to prioritize chemicals for further testing.

References

  1. Auso E, Lavado-Autric R, Cuevas E, Del Rey FE, Morreale De Escobar G, Berbel P. 2004. A moderate and transient deficiency of maternal thyroid function at the beginning of fetal neocorticogenesis alters neuronal migration. Endocrinology. Sep;145:4037-4047.
  2. Berbel P, Mestre JL, Santamaria A, Palazon I, Franco A, Graells M, Gonzalez-Torga A, de Escobar GM. 2009. Delayed neurobehavioral development in children born to pregnant women with mild hypothyroxinemia during the first month of gestation: the importance of early iodine supplementation. Thyroid : official journal of the American Thyroid Association. May;19:511-519.
  3. Bernal J. Thyroid hormone receptors in brain development and function. Nat Clin Pract Endocrinol Metab. 2007 Mar;3(3):249-59.
  4. Cooper, D.S., Kieffer, J.D., Halpern, R., Saxe, V., Mover, H., Maloof, F., and Ridgway, E.C. (1983). Propylthiouracil (PTU) pharmacology in the rat. II. Effects of PTU on thyroid function. Endocrinology 113:921–928.
  5. Gilbert ME, Sanchez-Huerta K, Wood C. 2015. Mild Thyroid Hormone Insufficiency During Development Compromises Activity-Dependent Neuroplasticity in the Hippocampus of Adult Male Rats. Endocrinology. Nov 25:en20151643.
  6. Gilbert ME, Ramos RL, McCloskey DP, Goodman JH. 2014. Subcortical band heterotopia in rat offspring following maternal hypothyroxinaemia: structural and functional characteristics. Journal of neuroendocrinology. Aug;26:528-541.
  7. Gilbert ME. 2011. Impact of low-level thyroid hormone disruption induced by propylthiouracil on brain development and function. Toxicological sciences : an official journal of the Society of Toxicology. Dec;124:432-445.
  8. Gilbert ME, McLanahan ED, Hedge J, Crofton KM, Fisher JW, Valentin-Blasini L, Blount BC. 2011. Marginal iodide deficiency and thyroid function: dose-response analysis for quantitative pharmacokinetic modeling. Toxicology. Apr 28;283:41-48.
  9. Goodman JH, Gilbert ME. 2007. Modest thyroid hormone insufficiency during development induces a cellular malformation in the corpus callosum: a model of cortical dysplasia. Endocrinology. Jun;148:2593-2597.
  10. Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J, O'Heir CE, Mitchell ML, Hermos RJ, Waisbren SE, Faix JD, Klein RZ. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med. 1999 Aug 19;341(8):549-55. PubMed PMID: 10451459.
  11. Henrichs J, Bongers-Schokking JJ, Schenk JJ, Ghassabian A, Schmidt HG, Visser TJ, Hooijkaas H, de Muinck Keizer-Schrama SM, Hofman A, Jaddoe VV, Visser W, Steegers EA, Verhulst FC, de Rijke YB, Tiemeier H. Maternal thyroid function during early pregnancy and cognitive functioning in early childhood: the generation R study. J Clin Endocrinol Metab. 2010 Sep;95(9):4227-34.
  12. Kooistra L, Crawford S, van Baar AL, Brouwers EP, Pop VJ. Neonatal effects of maternal hypothyroxinemia during early pregnancy. Pediatrics. 2006 Jan;117(1):161-7.
  13. Lavado-Autric R, Auso E, Garcia-Velasco JV, Arufe Mdel C, Escobar del Rey F, Berbel P, Morreale de Escobar G. 2003. Early maternal hypothyroxinemia alters histogenesis and cerebral cortex cytoarchitecture of the progeny. The Journal of clinical investigation. Apr;111:1073-1082.
  14. Morte B, Díez D, Ausó E, Belinchón MM, Gil-Ibáñez P, Grijota-Martínez C, Navarro D, de Escobar GM, Berbel P, Bernal J. Thyroid hormone regulation of gene expression in the developing rat fetal cerebral cortex: prominent role of the Ca2+/calmodulin-dependent protein kinase IV pathway. Endocrinology. 2010 Feb;151(2):810-20.
  15. Paul KB, Hedge JM, Rotroff DM, Hornung MW, Crofton KM, Simmons SO. Development of a thyroperoxidase inhibition assay for high-throughput screening. Chem Res Toxicol. 2014 Mar 17;27(3):387-99
  16. Pop VJ, Kuijpens JL, van Baar AL, Verkerk G, van Son MM, de Vijlder JJ, Vulsma T, Wiersinga WM, Drexhage HA, Vader HL. Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clin Endocrinol (Oxf). 1999 Feb;50(2):149-55
  17. Pop VJ, Brouwers EP, Vader HL, Vulsma T, van Baar AL, de Vijlder JJ. Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study. Clin Endocrinol (Oxf). 2003 Sep;59(3):282-8.
  18. Royland JE, Parker JS, Gilbert ME. 2008a. A genomic analysis of subclinical hypothyroidism in hippocampus and neocortex of the developing rat brain. Journal of neuroendocrinology. Dec;20:1319-1338.
  19. Royland JE, Wu J, Zawia NH, Kodavanti PR. 2008b. Gene expression profiles in the cerebellum and hippocampus following exposure to a neurotoxicant, Aroclor 1254: developmental effects. Toxicology and applied pharmacology. Sep 1;231:165-178.
  20. Shiraki A, Akane H, Ohishi T, Wang L, Morita R, Suzuki K, Mitsumori K, Shibutani M. 2012. Similar distribution changes of GABAergic interneuron subpopulations in contrast to the different impact on neurogenesis between developmental and adult-stage hypothyroidism in the hippocampal dentate gyrus in rats. Archives of toxicology. Oct;86:1559-1569.
  21. US EPA (2011) FIFRA Scintific Advisory Panel Consultation. Integrated Approaches to Testing and Assessment Strategy: Use of New Computational and Molecular Tools, US. May 24, 26, 2011, US Environmental Protection Agency, Office of Pesticide Programs, Washington DC
  22. Wei W, Wang Y, Wang Y, Dong J, Min H, Song B, Teng W, Xi Q, Chen J. 2013. Developmental hypothyroxinaemia induced by maternal mild iodine deficiency delays hippocampal axonal growth in the rat offspring. Journal of neuroendocrinology. Sep;25:852-862.
  23. Wheeler SM, Willoughby KA, McAndrews MP, Rovet JF. Hippocampal size and memory functioning in children and adolescents with congenital hypothyroidism. J Clin Endocrinol Metab. 2011 Sep;96(9):E1427-34.
  24. Wheeler SM, McAndrews MP, Sheard ED, Rovet J. Visuospatial associative memory and hippocampal functioning in congenital hypothyroidism. J Int Neuropsychol Soc. 2012 Jan;18(1):49-56.
  25. Willoughby KA, McAndrews MP, Rovet JF. Accuracy of episodic autobiographical memory in children with early thyroid hormone deficiency using a staged event. Dev Cogn Neurosci. 2014 Jul;9:1-11.
  26. Willoughby KA, McAndrews MP, Rovet JF. Effects of maternal hypothyroidism on offspring hippocampus and memory. Thyroid. 2014 Mar;24(3):576-84.
  27. Willoughby KA, McAndrews MP, Rovet J. Effects of early thyroid hormone deficiency on children's autobiographical memory performance. J Int Neuropsychol Soc. 2013 Apr;19(4):419-29.
  28. Zoeller RT, Crofton KM. Mode of action: developmental thyroid hormone insufficiency--neurological abnormalities resulting from exposure to propylthiouracil. Crit Rev Toxicol. 2005 35(8-9):771-81. Review. PubMed PMID: 16417044.