This AOP is licensed under a Creative Commons Attribution 4.0 International License.
Upregulation of Thyroid Hormone Catabolism via Activation of Hepatic Nuclear Receptors, and Subsequent Adverse Neurodevelopmental Outcomes in Mammals
Point of Contact
- Katie Paul Friedman
- Kevin Crofton
- Mary Gilbert
|Author status||OECD status||OECD project||SAAOP status|
|Not under active development||Under Development||1.9||Included in OECD Work Plan|
This AOP was last modified on June 04, 2021 10:11
|Activation, Pregnane-X receptor, NR1l2||September 16, 2017 10:14|
|Loss, Cochlear function||September 16, 2017 10:14|
|Thyroxine (T4) in neuronal tissue, Decreased||April 04, 2019 09:13|
|Thyroxine (T4) in serum, Decreased||November 14, 2020 02:14|
|Induction, Upregulation of glucuronyltransferase activity||September 16, 2017 10:14|
|Increase, Biliary excretion TH glucuronide||September 16, 2017 10:14|
|Hippocampal anatomy, Altered||August 11, 2018 09:36|
|Hippocampal Physiology, Altered||August 11, 2018 09:41|
|Hippocampal gene expression, Altered||August 11, 2018 09:26|
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).
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
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
|Sequence||Type||Event ID||Title||Short name|
|1||MIE||239||Activation, Pregnane-X receptor, NR1l2||Activation, Pregnane-X receptor, NR1l2|
|2||KE||295||Induction, Upregulation of glucuronyltransferase activity||Induction, Upregulation of glucuronyltransferase activity|
|3||KE||401||Increase, Biliary excretion TH glucuronide||Increase, Biliary excretion TH glucuronide|
|4||KE||281||Thyroxine (T4) in serum, Decreased||T4 in serum, Decreased|
|5||KE||280||Thyroxine (T4) in neuronal tissue, Decreased||T4 in neuronal tissue, Decreased|
|6||KE||756||Hippocampal gene expression, Altered||Hippocampal gene expression, Altered|
|7||KE||757||Hippocampal anatomy, Altered||Hippocampal anatomy, Altered|
|8||KE||758||Hippocampal Physiology, Altered||Hippocampal Physiology, Altered|
|9||AO||319||Loss, Cochlear function||Loss, Cochlear function|
Relationships Between Two Key Events (Including MIEs and AOs)
Life Stage Applicability
|Fetal to Parturition||Moderate|
Overall Assessment of the AOP
Domain of Applicability
Essentiality of the Key Events
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