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T4 in serum, Decreased leads to Hippocampal Physiology, Altered
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Inhibition of Thyroperoxidase and Subsequent Adverse Neurodevelopmental Outcomes in Mammals||non-adjacent||Moderate||Low||Kevin Crofton (send email)||Open for citation & comment||WPHA/WNT Endorsed|
Life Stage Applicability
|During brain development||High|
Key Event Relationship Description
Thyroid hormones are critical for normal development of the structure and function of the brain, including the hippocampus (Anderson et al., 2003; Bernal, 2007). Brain concentrations of T4 are dependent on transport of primarily T4 from serum, with subsequent conversion to T3 in the astrocytes by deiodinase and transfer to nuclear receptors within the neuron. This is followed by TH dependent gene transcription that influences hippocampal structural development and subsequent physiological function.
Evidence Supporting this KER
The weight of evidence for this indirect relationship is moderate. A wide variety studies have been performed in several labs in which thyroid hormone reductions in serum induced by chemicals/treatments, acting at a variety of target sites to disrupt hormonal status, is coincident with altered hippocampal physiology and/or plasticity. These include inhibition of TPO, NIS, dietary insufficiencies of iodine, and upregulation of liver catabolism, NIS inhibition, or dietary manipulation of iodine. Most of the data available is from the model TPO inhibitors, PTU and MMI, and this data documents enduring hippocampal physiological impairments in adult offspring following a period of transient serum TH insufficiencies in the pre- and post-natal period. Serum hormones are reported for the neonate and the dam at the termination of exposure, and recovery of hormonal status in the adult has been demonstrated in a number of studies despite the persistence of the hippocampal deficit. A few laboratories have reported dose-dependent effects at less than maximal hormone depletion.
The biological plausibility of this KER is rated as strong. The relationship is consistent with the known biology of how TH control development of hippocampal physiology.
Uncertainties and Inconsistencies
There are no inconsistencies in this KER, but there are some remaining uncertainties. It is widely accepted that changes in serum THs during development will result in alterations in behavior controlled by the hippocampus. This has been repeatedly demonstrated in animal models and in humans. However, most studies have been performed under conditions of severe hypothyroidism induced primarily by TPO-inhibitors MMI and PTU, or severe iodine deficiency. In addition, it is also known that there is an interaction between physiological and anatomical development, where anatomy develops first, and can be ‘reshaped’ by the ongoing maturation of physiological function (e.g., Kutsarova et al., 2017).
Insufficient data exist to date that could be used to develop a quantitative predictive model of neurophysiological in hippocampus from serum TH concentrations. The dynamic range over which neurophysiological endpoints can vary is small complicating the development of quantitative relationships between degree of TH insufficiency and magnitude of neurophysiological impairment.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Most of the data to support this KER are derived from rodent studies.
Anderson GW, Schoonover CM, Jones SA (2003) Control of thyroid hormone action in the developing rat brain. Thyroid 13:1039-56.
Bernal J. 2007. Thyroid hormone receptors in brain development and function. Nature clinical practice Endocrinology & metabolism. 3:249-259.
Dong J, Yin H, Liu W, Wang P, Jiang Y, Chen J. Congenital iodine deficiency and hypothyroidism impair LTP and decrease C-fos and C-jun expression in rat hippocampus. Neurotoxicol 2005; 26:417-426.
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