Upstream eventT4 in serum, Decreased
Hippocampal anatomy, Altered
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Inhibition of Thyroperoxidase and Subsequent Adverse Neurodevelopmental Outcomes in Mammals||non-adjacent||High||Low|
Life Stage Applicability
|During brain development||High|
Key Event Relationship Description
The vast majority of brain thyroxine (T4) is from the serum. Once taken up from the serum, T4 is converted to triiodothyronine (T3) which binds to the nuclear receptors (TRα and TRβ) to control thyroid-mediated gene expression (Oppenheimer, 1983). It is well established that TH regulates genes critical for brain development (Bernal, 2007; Anderson et al., 2003). As such, the structural development of the hippocampus is modulated by TR-mediated gene transcription, and alterations in serum TH can adversely impact hippocampal neuroanatomy.
Evidence Supporting this KER
The weight of evidence for this indirect relationship is strong. There is a vast amount of literature that supports this KER in multiple species.
The biological plausibility of this KER is rated as strong. The relationship is consistent with the known biology of the regulation of serum TH concentrations, brain TH concentrations, and the known action of TH to modulate genes critical for developmental processes that control structural development of the brain in general, including the hippocampus.
The empirical support for this KER is strong. In humans, untreated congenital hypothyroidism and severe iodine deficiency are accompanied by reductions in circulating levels of TH, and result in severe structural alterations in brain size, including hippocampus (Wheeler et al., 2011). The tie to serum TH has been amply demonstrated in clinical therapy of hypothyroidism during pregnancy and in congenitaly hypothyroid children born to euthroid mothers. In addition, there is a vast amount of data from animal studies that support this relationship. Gross structural changes in the hippocampus following severe TH insufficiency are widely reported (Hasegawa et al., 2010; Powell et al.,2010; Madiera et al., 1991; 1992; Rami et al. 1986a 1986b; Madeira and Paula-Barbosa 1993; Rabie et al., 1980; Berbel et al., 1996). Other studies reveal more subtle changes in hippocampal structure such as reductions in a specific subregions of the hippocampus or of a cell type (eg. parvalbumin expressing inhibitory neurons) or synaptic component (ie synapsin, postsynaptic density proteins) or misplacement of cells within the hippocampal cell layers (Berbel et al., 1997; 2010; Gilbert et al., 2007; Auso et al., 2003; Gilbert et al., 2016; Cattani et al., 2013). These observations at the histological level are correlated with reductions in serum T4. The most profound structural impairments are typically seen with severe reductions in both hormones.
Additional evidence for a relationship between serum TH and hippocampal anatomy comes from the study of adult neurogenesis. The propensity of the hippocampus to generate new neurons throughout the lifetime of the organism occurs in only two brain regions, the olfactory bulb and the hippocampus. Severe reductions in circulating levels of TH in adulthood reduces both neuroprogenitor cell proliferation and survival of newly generated neurons in the neurogenic niche of the hippocampal dentate gyrus (Ambrogini et al., 2005, Montero-Pedrazuela et al., 2006, Kapoor et al., 2015). These same effects on neurogenesis also occur during development. However, the impact of developmental TH disruption on neurogenesis in adult offspring shows that the developing brain is more sensitive to these persistent effects. For example, a reduction in the capacity for neurogenesis was recently demonstrated in adult euthyroid offspring of developmentally TH compromised dams (Gilbert et al., 2016). These data indicate a permanent deficit in the capacity for neurogenesis, a process that controls dentate gyrus volume and cell number, following moderate reductions in serum TH in the fetus/neonate.
Finally, from in vitro studies, T3 stimulation accelerates the formation of GABAergic boutons and alters the distribution of GABAergic axons among growing neurons in culture. This growth is dependent on both activity within the network and the presence of T3. It can be blocked by the T3 nuclear receptor antagonist, 1-850, or pharmacological block of synaptic activity (Westerholz et al., 2010; 2013). T3 is believed to have this effect by it action on synaptic pruning. This example reveals the dynamic interplay between synaptic activity and neuroanatomy in the developing nervous system (Kozorovitskiy 2012).
Temporal Evidence: The temporal nature of this KER is developmental (Seed et al., 2005). It is a well-recognized fact that there are critical developmental windows for disruption of the serum THs that result in altered hippocampal anatomy. Reductions in serum TH in the neonate produced alterations in hippocampal parvalbumin-expressing neurons while the same treatment in adulthood is without effect (Gilbert et al., 2007). In a rodent model of prenatal TH deficiency, decreased length and number of radial glial cells which are critical for neuronal migration was reversed by hormone replacement treatment to the dam (Pathak et al., 2011). Reversibility of cortical layering defects with thyroxine treatment have also been reported in models of maternal hypothyroidism (Pathak et al., 2011; Berbel et al., 2010; Mohan et al., 2012). In in vitro studies, temporal specificity of the influence of T3 on GABAergic synapses and synaptic pruning has also been demonstrated (Westerholz et al., 2013). In addition, clinical therapy of hypothyroidism during pregnancy, and in congenitally hypothyroid children born to euthroid mothers ameliorates most of the adverse impacts on the developing human brain.
Dose-Response Evidence: There are limited data available to inform the dose-dependent nature of the correlation between serum THs and changes in hippocampal anatomy. Gilbert et al (2007) demonstrated dose-dependent declines in the expression of protein marker inhibitory neurons in both hippocampus and neocortex with graded exposures to PTU and resultant serum T4. Shiraki et al. (2014; 2016) report dose-dependent alterations in the expression patterns of several neuronal and glial protein markers in the hippocampus after developmental exposure to different doses of PTU or MMI. Gilbert et al. (2016) report dose-dependent reductions in linear morphometry and volume of hippocampal subfields following developmental exposure to the PTU.
Uncertainties and Inconsistencies
This has been repeatedly demonstrated. However, with some studies noted above, most investigations have been conducted in the neonate after severe hormone reductions induced by PTU, MMI or thyroidectomy. These severe changes alter a wide variety of general growth and developmental processes. In one of the few dose-response studies assessing hippocampal anatomy, alterations in simple guidenline metrics of linear morphometry and volume of hippocampal subfields following developmental exposure to the PTU were largely restricted to the high dose group, despite alterations in downstream KEs of hippocampal physiology and cognitive function. This may result from inadequacy of the assessment tools or the timing of the observations. Similarly, in chemically induced serum hormone reductions of comparable magnitude as those induced by PTU or MMI, observations of hippocampal morphology are not always seen (PTU vs ETU or mancozeb, European Commission, 2017). Consideration of the sensitivity of neuroanatomical and neurobehavioral method used, as well as chemical kinetics that drive the reduction of maternal, fetal, or neonatal TH reduction, may be key to understanding these discrepancies. More data is needed that link more limited decrements in serum TH to specific hippocampal anatomical changes. The role of direct fetal TPO inhibition contribution to fetal TH and subsequent changes to hippocampal structure and subsequent downstream KEs in humans is a knowledge gap.
Quantitative Understanding of the Linkage
Most investigations for hippocampal anatomy have been conducted in the neonate after severe hormone reductions. There is currently insufficient data for quantitative analysis of serum T4 and hippocampal neuroanatomy.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Most of the available data has come from rodent models. Human clinincal studies have documented changes in hippocampal volume in children with congenital hypothyroidism (Wheeler et al., 2011).
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