Aop:8

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Status

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AOP Title

Upregulation of Thyroid Hormone Catabolism via Activation of Hepatic Nuclear Receptors, and Subsequent Adverse Neurodevelopmental Outcomes in Mammals
Short name: Nuclear receptor induced TH Catabolism and Developmental Hearing Loss

Authors

Katie Paul Friedman, Bayer CropScience, RTP, NC USA <katie.paulfriedman@bayer.com>

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>

Status

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Under development: Do not distribute or cite.

OECD Project 1.9: Upregulation of Thyroid Hormone Catabolism via Activation of Hepatic Nuclear Receptors, and Subsequent Adverse Neurodevelopmental Outcomes in Mammals.

This AOP was last modified on 12/5/2016.

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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).

Summary of the AOP

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Molecular Initiating Event

Molecular Initiating Event Support for Essentiality
Pregnane-X receptor, NR1l2, Activation Moderate

Key Events

Event Support for Essentiality
Upregulation of glucuronyltransferase activity, Induction Strong
Biliary excretion TH glucuronide, Increase Moderate
Thyroxin (T4) in serum, Decreased Strong
Thyroxine (T4) in neuronal tissue, Decreased Strong
Hippocampal gene expression, Altered Moderate
Hippocampal anatomy, Altered Moderate
Hippocampal function, Decreased Moderate

Adverse Outcome

Adverse Outcome
Cochlear function, Loss

Relationships Among Key Events and the Adverse Outcome

Event Description Triggers Weight of Evidence Quantitative Understanding
Pregnane-X receptor, NR1l2, Activation Directly Leads to Upregulation of glucuronyltransferase activity, Induction Strong Weak
Constitutive androstane receptor, NR1l3, Activation Directly Leads to Upregulation of glucuronyltransferase activity, Induction Moderate Weak
Upregulation of glucuronyltransferase activity, Induction Indirectly Leads to Serum thyroxine (T4), Decrease Strong Weak
Hepatic transporter gene expression, Up Regulation Indirectly Leads to Hepatic transport of parent T4, Increase Moderate
Biliary excretion TH glucuronide, Increase Directly Leads to Serum thyroxine (T4), Decrease Moderate Weak
Serum thyroxine (T4), Decrease Directly Leads to Tissue thyroid hormone concentration, Decrease Moderate Weak
Tissue thyroid hormone concentration, Decrease Indirectly Leads to TR-regulated cochlear proteins, Decrease Weak
TR-regulated cochlear proteins, Decrease Directly Leads to Structure of the cochlea, Damage Weak
Structure of the cochlea, Damage Directly Leads to Cochlear function, Loss Moderate
Pregnane-X receptor, NR1l2, Activation Directly Leads to Hepatic transporter gene expression, Up Regulation Moderate
Upregulation of glucuronyltransferase activity, Induction Directly Leads to Biliary excretion TH glucuronide, Increase Moderate

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Life Stage Applicability

Life Stage Evidence Links
Fetal to Parturition Moderate
Nursing Child Moderate

Taxonomic Applicability

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Sex Applicability

Sex Evidence Links

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Overall Assessment of the AOP

Weight of Evidence Summary

Summary Table
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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








Essentiality of the Key Events

Molecular Initiating Event Summary, Key Event Summary
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Quantitative Considerations

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Applicability of the AOP

Life Stage Applicability, Taxonomic Applicability, Sex Applicability
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References