Upstream eventT4 in serum, Decreased
Cognitive Function, Decreased
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||Moderate|
|XX Inhibition of Sodium Iodide Symporter and Subsequent Adverse Neurodevelopmental Outcomes in Mammals||non-adjacent||High||Moderate|
|Sodium Iodide Symporter (NIS) Inhibition and Subsequent Adverse Neurodevelopmental Outcomes in Mammals||non-adjacent||High||Low|
Life Stage Applicability
|During brain development||High|
Key Event Relationship Description
Thyroid hormones (TH) are critical for normal development of the structure and function of the brain, including hippocampal development and cognitive function (Anderson et al., 2003; Bernal, 2007; Willoughby et al., 2014). Brain concentrations of T4 are dependent on transfer of T4 from serum, through the vascular endothelia, into astrocytes. In astrocytes, T4 is converted to T3 by deiodinase and subsequently transferred to neurons cellular membrane transporters. In the brain T3 controls transcription and translation of genes responsible for normal hippocampal structural and functional development. Clearly the brain circuitry controlling cognitive function is complex and is not solely accomplished by the functionality of the hippocampus. However, it is well documented that normal hippocampal structure and physiology are critical for the development of cognitive function. Thus, there is an indisputable indirect link between serum T4 and cognitive function.
Evidence Supporting this KER
The weight of evidence for this indirect relationship is strong. Alterations in serum TH concentrations are very well correlated with adverse impacts on cognitive behaviors such as learning and memory. This includes a large amount of literature, from more than four decades of research, that links hypothyroidism and/or hypothyroxinemia with alterations in spatial cognitive function, a hippocampal dependent behavior. A number of reviews are cited below that are primarily from humans and rodents, but this indirect relationship has also been shown for a number of other species.
In humans, severe serum TH reductions that accompany congenital hypothyroidism dramatically impair brain function and lead to severe mental retardation. Lower global IQ scores, language delays and weak verbal skills, motor weakness, attentional deficits and learning impairments accompany low serum TH in children (Derksen-Lubsen and Verkerk 1996). Standard tests of IQ function in children born to mothers with even marginal hypothyoidism during pregnancy or in children with a defective thyroid gland who are then treated remain approximately 6 points below expected values. Selective deficits on visual spatial, motor, language, memory and attention tests are observed, the exact phenotype largely dependent on the developmental window over which the insufficiency occurred and the severity of the hormone deficit (Mirabella et al. 2000; Rovet 2002; Zoeller and Rovet 2004; Willoughby et al 2014). Indeed, this link is recognized as being so clinically important that T4 and TSH are monitored in all newborns in the US.
In rodent models, reductions in serum TH induced by TPO inhibitors such as MMI and PTU, when induced during development, lead to a variety of neurobehavioral impairments. These impairments can occur in the sensory, motor, and cognitive domains. The specific phenotype is dependent on both the window of exposure, the duration of exposure, and the severity of the hormone reduction (Zoeller and Rovet, 2004). This includes more than four decades of work linking serum TH changes to alterations in hippocampal-dependent spatial behaviors (Akaike et al., 2004; Axelstand etal., 2008; Brosvic et al; Kawada et al, 1988; Friedhoff et al, 2000; Gilbert and Sui, 2006; Gilbert et al., 2016; Gilbert, 2011).
The biological plausibility of this KER is rated as strong. The relationship is consistent with the known biology of how the relationship between serum TH concentrations, brain TH concentrations, and TH control of brain development.
Empirical support for this KER is rated as strong. Empirical data from studies that measure serum TH concentrations and then assess alterations in cognitive function, including hippocampal dependent behaviors, is vast. The qualitative relationship between reduced serum hormone levels and adverse cognitive outcomes is well accepted in endocrinology, as well as developmental neuroendocrinology. Indeed, the relationship between serum T4 and T3 levels and adverse neurodevelopmental outcomes (e.g., IQ loss in children) is beyond reproach.
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 cognitive function. In humans, hormone insufficiency that occurs in mid-pregnancy due to maternal drops in serum hormone, and that which occurs in late pregnancy due to disruptions in the fetal thyroid gland lead to different patterns of cognitive impairment (Zoeller and Rovet, 2004). In animal models, deficits in hippocampal-dependent cognitive tasks result from developmental, but not adult hormone deprivation (Gilbert and Sui, 2006; Gilbert et al., 2016; Axelstad et al, 2009; Gilbert, 2011; Opazo et al., 2008). Replacement studies have demonstrated that varying adverse neurobehavioral outcomes, including cognitive function, can be reduced or eliminated if T4 (and/or T3) treatment is given during the critical windows (e.g., Kawada et al., 1988; Goldey and Crofton, 1998; Reid et al., 2007).
Dose-Response Evidence: An increasing amount of literature is now available that provides clear evidence of the ‘dose-response’ nature of this KER. Most research over that last 40 years has employed high doses of chemicals, or chemicals plus thyroidectomies, that results in severe depletion of circulating thyroid hormones. More recently, researchers produced graded degrees of TH insufficiency in dams and pups by administering varying doses of chemicals and have correlated them to the dose-dependency of the observed effects. This work has provided increased confidence in the relationship between serum TH decrements and a variety of neurodevelopmental impairments, and also to the specificity of the observed effects on brain development that is directly mediated by TH insufficiency (Goldey et al., 1995; Crofton, 2004; Gilbert and Sui, 2006; Gilbert, 2011; Bastian et al., 2014; Royland et al., 2008; Sharlin et al., 2008).
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. A major uncertainty is the precise relationship between the degree, timing and duration of serum TH changes that leads to these behavioral deficits.
Inconsistencies may also exist for chemicals other than classical TPO inhibitors that may reduce serum TH and induce impairments in cognitive function, but through action on other endocrine systems, or via direct action on the brain in the absence of an intervening endocrine action.
Quantitative Understanding of the Linkage
Except for a quantitative relationship between serum T4 and hearing loss in rodents (Crofton, 2004), there are no other reports of development of quantitative predictive models linking serum TH and adverse neurological outcomes. Insufficient data exist to develop a quantitative predictive model of adverse cognitive outcomes from serum TH concentrations. However, evidence from human studies suggests that decreases as low as 25% in serum T4 in pregnant women will yield small decrements in IQ in children (e.g., Haddow et al., 1995). Since publication of this seminal paper, several reports have appeared providing supportive if not direct confirmatory data on the association of reductions in maternal or early postnatal serum TH and adverse neurodevelopmental outcomes (e.g., Rovet and Willoughby, 2010, Wheeler et al., 2011, Willoughby et al., 2014, Wheeler et al., 2015; Pop et al., 1999, Pop et al., 2003, Kooistra et al., 2006, Henrichs et al., 2010, Korevaar et al., 2016). Based on these data, regulatory authorities have used 10 and/or 20% changes in serum T4 as a point of departure for hazard assessments in rodent studies (EPA, 2011).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
There is a plethora of data supporting this KER in rats, mice, and humans.
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