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Symporter (NIS) Leads Sharon Munn, to Learning and Memory Anna Bal-Price Impairment

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Symporter (NIS) Leads Sharon Munn, to Learning and Memory Anna Bal-Price Impairment OECD Series on Adverse Outcome Pathways No. 14 Adverse Outcome Pathway Alexandra Rolaki, on inhibition of Na+/I- Francesca Pistollato, symporter (NIS) leads Sharon Munn, to learning and memory Anna Bal-Price impairment https://dx.doi.org/10.1787/7ca86a34-en │ 1 Adverse Outcome Pathway on Inhibition of Na+/I- symporter (NIS) leads to learning and memory impairment Series on Adverse Outcome Pathways No. 14 2 │ Foreword This Adverse Outcome Pathway (AOP) on Inhibition of Na+/I- symporter (NIS) leads to learning and memory impairment, has been developed under the auspices of the OECD AOP Development Programme, overseen by the Extended Advisory Group on Molecular Screening and Toxicogenomics (EAGMST), which is an advisory group under the Working Group of the National Coordinators for the Test Guidelines Programme (WNT). The AOP has been reviewed internally by the EAGMST, externally by experts nominated by the WNT, and has been endorsed by the WNT and the Working Party on Hazard Assessment (WPHA) in May 2019. Through endorsement of this AOP, the WNT and the WPHA express confidence in the scientific review process that the AOP has undergone and accept the recommendation of the EAGMST that the AOP be disseminated publicly. Endorsement does not necessarily indicate that the AOP is now considered a tool for direct regulatory application. The Joint Meeting of the Chemicals Committee and the Working Party on Chemicals, Pesticides and Biotechnology agreed to declassification of this AOP on 26 June 2019. This document is being published under the responsibility of the Joint Meeting of the Chemicals Committee and the Working Party on Chemicals, Pesticides and Biotechnology. The outcome of the internal and external reviews are publicly available respectively in the AOP Wiki and the eAOP Portal of the AOP Knowledge Base at the following links: [internal review] [external review]. │ 3 Table of contents Foreword ................................................................................................................................................ 2 Adverse Outcome Pathway on Inhibition of Na+/I- symporter (NIS) leads to learning and memory impairment .............................................................................................................................. 5 Short Title: NIS inhibition and learning and memory impairment ...................................................... 5 Authors ............................................................................................................................................. 5 Abstract .................................................................................................................................................. 6 Graphical Representation ..................................................................................................................... 7 Summary of the AOP ............................................................................................................................ 8 Molecular Initiating Events (MIE), Key Events (KE), Adverse Outcomes (AO) ............................... 8 Key Event Relationships ...................................................................................................................... 8 Stressors ............................................................................................................................................... 9 Overall Assessment of the AOP .......................................................................................................... 10 Domain of Applicability .................................................................................................................... 12 Life Stage Applicability ................................................................................................................. 12 Taxonomic Applicability ................................................................................................................ 12 Sex Applicability ............................................................................................................................ 13 Essentiality of the Key Events ........................................................................................................... 13 Quantitative Consideration ................................................................................................................ 21 Considerations for Potential Applications of the AOP (optional) ................................................... 22 References ............................................................................................................................................ 23 Appendix 1 ........................................................................................................................................... 35 List of MIEs in this AOP ................................................................................................................... 35 Event: 424: Inhibition, Na+/I- symporter (NIS) ............................................................................. 35 List of Key Events in the AOP .......................................................................................................... 48 Event: 425: Decrease of Thyroidal iodide ...................................................................................... 48 Event: 277: Thyroid hormone synthesis, Decreased ...................................................................... 53 Event: 281: Thyroxine (T4) in serum, Decreased .......................................................................... 59 Event: 280: Thyroxine (T4) in neuronal tissue, Decreased ............................................................ 66 Event: 381: Reduced levels of BDNF ............................................................................................ 72 Event: 851: Decrease of GABAergic interneurons ........................................................................ 77 Event 385:Decrease of synaptogenesis .......................................................................................... 83 Event: 386: Decrease of neuronal network function ...................................................................... 87 List of Adverse Outcomes in this AOP .............................................................................................. 92 Event: 341: Impairment, Learning and memory ............................................................................ 92 Appendix 2: List of Key Event Relationships in the AOP ............................................................. 100 List of Adjacent Key Event Relationships ....................................................................................... 100 Relationship: 442: Inhibition, Na+/I- symporter (NIS) leads to Thyroidal Iodide, Decreased .... 100 Relationship: 872: Thyroidal Iodide, Decreased leads to TH synthesis, Decreased .................... 109 Relationship: 305: TH synthesis, Decreased leads to T4 in serum, Decreased ............................ 116 4 │ Relationship: 312: T4 in serum, Decreased leads to T4 in neuronal tissue, Decreased ............... 121 Relationship: 444: T4 in neuronal tissue, Decreased leads to BDNF, Reduced .......................... 127 Relationship: 870: BDNF, Reduced leads to GABAergic interneurons, Decreased .................... 138 Relationship: 871: GABAergic interneurons, Decreased leads to Synaptogenesis, Decreased ... 145 Relationship: 358: Synaptogenesis, Decreased leads to Neuronal network function, Decreased 152 Relationship: 359: Neuronal network function, Decreased leads to Impairment, Learning and memory ........................................................................................................................................ 159 List of Non Adjacent Key Event Relationships ............................................................................... 173 Relationship: 1503: Inhibition, Na+/I- symporter (NIS) leads to Impairment, Learning and memory ........................................................................................................................................ 173 Relationship: 1506: TH synthesis, Decreased leads to Impairment, Learning and memory ........ 183 Relationship: 1504: TH synthesis, Decreased leads to BDNF, Reduced ..................................... 190 Relationship: 1505: TH synthesis, Decreased leads to GABAergic interneurons, Decreased ..... 196 Relationship: 448: BDNF, Reduced leads to Synaptogenesis, Decreased ................................... 201 Relationship: 1507: BDNF, Reduced leads to Impairment, Learning and memory ..................... 208 │ 5 Adverse Outcome Pathway on Inhibition of Na+/I- symporter (NIS) leads to learning and memory impairment Short Title: NIS inhibition and learning and memory impairment Authors Alexandra Rolaki, Francesca Pistollato, Sharon Munn and Anna Bal-Price* (*corresponding author: [email protected]) European Commission Joint Research Centre, Directorate F - Health, Consumers and Reference Materials, Ispra, Italy 6 │ Abstract The thyroid hormones (TH) are essential for brain development, maturation, and function as they regulate the early key developmental processes such as neurogenesis, cell migration, proliferation, myelination and neuronal and glial differentiation. Normal human brain development and cognitive function relays on sufficient production of TH during the perinatal period. The function of Na+/I- symporter (NIS) is critical for the physiological
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