API

Aop: 8

AOP Title

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Upregulation of Thyroid Hormone Catabolism via Activation of Hepatic Nuclear Receptors, and Subsequent Adverse Neurodevelopmental Outcomes in Mammals

Short name:

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Nuclear receptor induced TH Catabolism and Developmental Hearing Loss

Authors

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

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

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

Point of Contact

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Katie Paul Friedman

Contributors

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  • Katie Paul Friedman
  • Kevin Crofton
  • Mary Gilbert

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development 1.9 Included in OECD Work Plan


This AOP was last modified on October 06, 2017 10:37

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Revision dates for related pages

Page Revision Date/Time
Activation, Pregnane-X receptor, NR1l2 September 16, 2017 10:14
Loss, Cochlear function September 16, 2017 10:14
Thyroxine (T4) in neuronal tissue, Decreased September 17, 2017 17:11
Thyroxine (T4) in serum, Decreased September 17, 2017 18:37
Induction, Upregulation of glucuronyltransferase activity September 16, 2017 10:14
Increase, Biliary excretion TH glucuronide September 16, 2017 10:14
Hippocampal anatomy, Altered September 16, 2017 10:14
Hippocampal Physiology, Altered September 17, 2017 17:17
Hippocampal gene expression, Altered September 17, 2017 17:14

Abstract

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Data from rodent studies demonstrate that thyroid hormone disruption during cochlear development culminates in ototoxicity. Developmental exposure of rats to polychlorinated biphenyls (PCBs) results in a low-frequency hearing loss in adult offspring (Goldey et al., 1995a; Herr et al., 1996; 2001; Crofton and Rice, 1999; Laskey et al., 2002). A body of work now supports the hypothesis that this ototoxicity results from PCB-induced hypothyroxinemia during a critical period of auditory development. Evidence for this hypothesis includes: a correlation between the severity of functional auditory impairment and the degree of thyroid hormone depletion (Goldey et al., 1995a; 1995b; Goldey and Crofton, 1998; Crofton, 2004), a cross-fostering study demonstrating that the critical exposure period is postnatal (Crofton et al., 2000a), and amelioration of the hearing loss following postnatal thyroxine replacement (Goldey and Crofton, 1998). Below an adverse outcome pathway is described for chemicals that activate xenobiotic nuclear receptors, including AhR, CAR, and PXR, leading to thyroid hormone disruption during cochlear development and resulting in permanent auditory loss.

This AOP is a revision and update of the original started on the Chemical Mode of Action wiki sponsored by WHO/IPCS. This MOA was described and published by Crofton and Zoeller 2005).


Background (optional)

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This AOP is an update of the WHO/IPCS MOA developed in 2005 by Crofton and Zoeller (Crit Rev Toxicol 2005).

Crofton KM, Zoeller RT. Mode of action: neurotoxicity induced by thyroid hormone disruption during development--hearing loss resulting from exposure to PHAHs. Crit Rev Toxicol. 2005 Oct-Nov;35(8-9):757-69. PMID: 6417043


Summary of the AOP

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Stressors

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Molecular Initiating Event

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Title Short name
Activation, Pregnane-X receptor, NR1l2 Activation, Pregnane-X receptor, NR1l2

Key Events

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Title Short name
Thyroxine (T4) in neuronal tissue, Decreased T4 in neuronal tissue, Decreased
Thyroxine (T4) in serum, Decreased T4 in serum, Decreased
Induction, Upregulation of glucuronyltransferase activity Induction, Upregulation of glucuronyltransferase activity
Increase, Biliary excretion TH glucuronide Increase, Biliary excretion TH glucuronide
Hippocampal anatomy, Altered Hippocampal anatomy, Altered
Hippocampal Physiology, Altered Hippocampal Physiology, Altered
Hippocampal gene expression, Altered Hippocampal gene expression, Altered

Adverse Outcome

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Title Short name
Loss, Cochlear function Loss, Cochlear function

Relationships Between Two Key Events (Including MIEs and AOs)

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Network View

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Life Stage Applicability

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Life stage Evidence
Fetal to Parturition Moderate
Nursing Child Moderate

Taxonomic Applicability

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Sex Applicability

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Graphical Representation

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Click to download graphical representation template

W1siziisijiwmtyvmtevmjkvndq4mza1mjyyx051y2xlyxjfcmvjzxb0b3jfywn0axzhdglvbl9hbmrfb3rvdg94awnpdhkuanbnil0swyjwiiwidgh1bwiilci1mdb4ntawil1d?sha=756dca4c48a7069d

Overall Assessment of the AOP

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Domain of Applicability

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Essentiality of the Key Events

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Weight of Evidence Summary

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Summary Table
Provide an overall summary of the weight of evidence based on the evaluations of the individual linkages from the Key Event Relationship pages.

Concordance of dose-response relationships

Multiple studies provide limited (2-3 doses) dose-response data for many of the key events. These studies demonstrate similar magnitudes of effect on circulating hormones for doses of PCBs that are within an order of magnitude (3-25 mg/kg/day for Aroclor 1254) (e.g.,Morse et al., 1996; Goldey et al., 1998). Very limited data are available correlating any of the key events. One exception is the relationship between circulating serum T4 concentrations during development and the magnitude of hearing loss (Crofton, 2004). There is a very good correlation between total serum T4 concentrations on postnatal day (PND) 14 and hearing loss assessed in adult offspring of PCB exposed dams (Figure 2). All of these events occur within a 2-3 fold dose range.

 


Temporal concordance among the key events and the adverse outcome Strength, consistency, and specificity of association of adverse effect and initiating event Biological plausibility, coherence, and consistency of the experimental evidence Alternative mechanism(s) or MIE(s) that logically present themselves and the extent to which they may detract from the AOP Uncertainties, inconsistencies, and data gaps

 

 

 

 

 

 

 


Quantitative Considerations

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Considerations for Potential Applications of the AOP (optional)

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References

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