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AOP: 8
Title
Upregulation of Thyroid Hormone Catabolism via Activation of Hepatic Nuclear Receptors, and Subsequent Adverse Neurodevelopmental Outcomes in Mammals
Short name
Graphical Representation
Point of Contact
Contributors
- Katie Paul Friedman
- Kevin Crofton
- Mary Gilbert
Coaches
OECD Information Table
OECD Project # | OECD Status | Reviewer's Reports | Journal-format Article | OECD iLibrary Published Version |
---|---|---|---|---|
1.9 | Under Development |
This AOP was last modified on April 29, 2023 16:02
Revision dates for related pages
Page | Revision Date/Time |
---|---|
Activation, Pregnane-X receptor, NR1l2 | December 03, 2024 10:03 |
Loss, Cochlear function | September 16, 2017 10:14 |
Thyroxine (T4) in neuronal tissue, Decreased | April 04, 2019 09:13 |
Thyroxine (T4) in serum, Decreased | October 10, 2022 08:52 |
Induction, Upregulation of glucuronyltransferase activity | September 16, 2017 10:14 |
Hippocampal anatomy, Altered | July 24, 2024 23:09 |
Hippocampal Physiology, Altered | July 24, 2024 23:15 |
Hippocampal gene expression, Altered | August 11, 2018 09:26 |
Increased, Clearance of thyroxine from serum | January 26, 2021 10:41 |
Activation, Pregnane-X receptor, NR1l2 leads to Induction, Upregulation of glucuronyltransferase activity | September 14, 2021 12:29 |
Induction, Upregulation of glucuronyltransferase activity leads to Increased, Clearance of thyroxine from serum | September 10, 2021 08:32 |
Increased, Clearance of thyroxine from serum leads to T4 in serum, Decreased | January 26, 2021 10:42 |
T4 in serum, Decreased leads to T4 in neuronal tissue, Decreased | April 04, 2019 10:50 |
T4 in neuronal tissue, Decreased leads to Hippocampal gene expression, Altered | August 11, 2018 19:18 |
Hippocampal gene expression, Altered leads to Hippocampal anatomy, Altered | August 11, 2018 19:05 |
Hippocampal anatomy, Altered leads to Hippocampal Physiology, Altered | July 25, 2024 18:38 |
Hippocampal Physiology, Altered leads to Loss, Cochlear function | September 14, 2021 12:35 |
Abstract
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).
AOP Development Strategy
Context
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
Strategy
Summary of the AOP
Events:
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
Type | Event ID | Title | Short name |
---|
MIE | 239 | Activation, Pregnane-X receptor, NR1l2 | Activation, Pregnane-X receptor, NR1l2 |
KE | 295 | Induction, Upregulation of glucuronyltransferase activity | Induction, Upregulation of glucuronyltransferase activity |
KE | 961 | Increased, Clearance of thyroxine from serum | Increased, Clearance of thyroxine from serum |
KE | 281 | Thyroxine (T4) in serum, Decreased | T4 in serum, Decreased |
KE | 280 | Thyroxine (T4) in neuronal tissue, Decreased | T4 in neuronal tissue, Decreased |
KE | 756 | Hippocampal gene expression, Altered | Hippocampal gene expression, Altered |
KE | 757 | Hippocampal anatomy, Altered | Hippocampal anatomy, Altered |
KE | 758 | Hippocampal Physiology, Altered | Hippocampal Physiology, Altered |
AO | 319 | Loss, Cochlear function | Loss, Cochlear function |
Relationships Between Two Key Events (Including MIEs and AOs)
Title | Adjacency | Evidence | Quantitative Understanding |
---|
Network View
Prototypical Stressors
Life Stage Applicability
Life stage | Evidence |
---|---|
Fetal to Parturition | Moderate |
Nursing Child | Moderate |
Taxonomic Applicability
Term | Scientific Term | Evidence | Link |
---|---|---|---|
rat | Rattus norvegicus | NCBI |
Sex Applicability
Overall Assessment of the AOP
Domain of Applicability
Essentiality of the Key Events
Evidence Assessment
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