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Relationship: 403

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

T4 in serum, Decreased leads to Cognitive Function, Decreased

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

T4 in serum, Decreased

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Cognitive Function, Decreased

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

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	High	Moderate	Evgeniia Kazymova (send email)	Open for citation & comment	WPHA/WNT Endorsed
XX Inhibition of Sodium Iodide Symporter and Subsequent Adverse Neurodevelopmental Outcomes in Mammals	non-adjacent	High	Moderate	Evgeniia Kazymova (send email)	Not under active development
Sodium Iodide Symporter (NIS) Inhibition and Subsequent Adverse Neurodevelopmental Outcomes in Mammals	non-adjacent	High	Low	Evgeniia Kazymova (send email)	Under Development: Contributions and Comments Welcome
AhR activation in the liver leading to Subsequent Adverse Neurodevelopmental Outcomes in Mammals	non-adjacent	High	High	Cataia Ives (send email)	Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
rat	Rattus norvegicus	High	NCBI
mouse	Mus musculus	High	NCBI
human	Homo sapiens	High	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Male	High
Female	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
During brain development	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

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 Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

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).

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

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 Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

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

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

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.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

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).

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

There is a plethora of data supporting this KER in rats, mice, and humans.

References

List of the literature that was cited for this KER description. More help

Akaike M, Kato N, Ohno H, Kobayashi T (1991) Hyperactivity and spatial maze learning impairment of adult rats with temporary neonatal hypothyroidism. Neurotoxicol Teratol 13:317-322.

Anderson GW, Schoonover CM, Jones SA (2003) Control of thyroid hormone action in the developing rat brain. Thyroid 13:1039-56.

Axelstad M, Hansen PR, Boberg J, Bonnichsen M, Nellemann C, Lund SP, Hougaard KS, Hass U. Developmental neurotoxicity of propylthiouracil (PTU) in rats: relationship between transient hypothyroxinemia during development and long-lasting behavioural and functional changes. Toxicol Appl Pharmacol. 2008 Oct 1;232(1):1-13

Bastian TW, Prohaska JR, Georgieff MK, Anderson GW (2014) Fetal and neonatal iron deficiency exacerbates mild thyroid hormone insufficiency effects on male thyroid hormone levels and brain thyroid hormone-responsive gene expression. Endocrinology 155:1157-1167.

Bernal J. 2007. Thyroid hormone receptors in brain development and function. Nature clinical practice Endocrinology & metabolism. 3:249-259.

Brosvic GM, Taylor JN, Dihoff RE. (2002). Influences of early thyroid hormone manipulations: delays in pup motor and exploratory behavior are evident in adult operant performance. Physiol Behav. Apr 15;75(5):697-715.

Crofton KM. Developmental disruption of thyroid hormone: correlations with hearing dysfunction in rats. Risk Anal. 2004 Dec;24(6):1665-71.

Derksen-Lubsen, G. and P. H. Verkerk (1996). "Neuropsychologic development in early treated congenital hypothyroidism: analysis of literature data." Pediatr Res 39(3): 561-6.

EPA (2011) FIFRA Scientific Advisory Panel Consultation, Integrated Approaches to Testing and Assessment Strategy:Use of New Computational and Molecular Tools, US Environmental Protection Agency, Office of Pesticide Programs, Washington DC May 24-26, 2011.

Friedhoff AJ, Miller JC, Armour M, Schweitzer JW, Mohan S. Role of maternal biochemistry in fetal brain development: effect of maternal thyroidectomy on behaviour and biogenic amine metabolism in rat progeny. Int J Neuropsychopharmacol. 2000 Jun;3(2):89-97.

Gilbert ME. Impact of low-level thyroid hormone disruption induced by propylthiouracil on brain development and function. Toxicol Sci. 2011;124(2):432-445.

Gilbert ME, Sui L. Dose-dependent reductions in spatial learning and synaptic function in the dentate gyrus of adult rats following developmental thyroid hormone insufficiency. Brain Res. 2006 Jan 19;1069(1):10-2

Gilbert ME, Sanchez-Huerta K, Wood C (2016) Mild Thyroid Hormone Insufficiency During Development Compromises Activity-Dependent Neuroplasticity in the Hippocampus of Adult Male Rats. Endocrinology 157:774-787.

Goldey ES, Kehn LS, Rehnberg GL, Crofton KM. Effects of developmental hypothyroidism on auditory and motor function in the rat. Toxicol Appl Pharmacol. 1995 Nov;135(1):67-76.

Goldey ES, Crofton KM. (1998) Thyroxine replacement attenuates hypothyroxinemia, hearing loss, and motor deficits following developmental exposure to Aroclor 1254 in rats. Toxicol Sci. 45:94-105.

Haddow, J. E., G. E. Palomaki, et al. (1999). "Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child." N Engl J Med 341(8): 549-55.

Henrichs J, Bongers-Schokking JJ, Schenk JJ, Ghassabian A, Schmidt HG, Visser TJ, Hooijkaas H, de Muinck Keizer-Schrama SM, Hofman A, Jaddoe VV, Visser W, Steegers EA, Verhulst FC, de Rijke YB, Tiemeier H (2010) Maternal thyroid function during early pregnancy and cognitive functioning in early childhood: the generation R study. J Clin Endocrinol Metab 95:4227-4234.

Kawada J, Mino H, Nishida M, Yoshimura Y. (1988) An appropriate model for congenital hypothyroidism in the rat induced by neonatal treatment with propylthiouracil and surgical thyroidectomy: studies on learning ability and biochemical parameters. Neuroendocrinology. 47:424-30.

Kooistra L, Crawford S, van Baar AL, Brouwers EP, Pop VJ (2006) Neonatal effects of maternal hypothyroxinemia during early pregnancy. Pediatrics 117:161-167.

Korevaar TI, Muetzel R, Medici M, Chaker L, Jaddoe VW, de Rijke YB, Steegers EA, Visser TJ, White T, Tiemeier H, Peeters RP (2016) Association of maternal thyroid function during early pregnancy with offspring IQ and brain morphology in childhood: a population-based prospective cohort study. Lancet Diabetes Endocrinol 4:35-43.

Mirabella, G., D. Feig, et al. (2000). "The effect of abnormal intrauterine thyroid hormone economies on infant cognitive abilities." J Pediatr Endocrinol Metab 13(2): 191-4.

Opazo MC, Gianini A, Pancetti F, Azkcona G, Alarcón L, Lizana R, Noches V, Gonzalez PA, Marassi MP, Mora S, Rosenthal D, Eugenin E, Naranjo D, Bueno SM, Kalergis AM, Riedel CA (2008), Maternal hypothyroxinemia impairs spatial learning and synaptic nature and function in the offspring. Endocrinology 149:5097-5106.

Pop VJ, Brouwers EP, Vader HL, Vulsma T, van Baar AL, de Vijlder JJ (2003) Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study. Clin Endocrinol (Oxf) 59:282-288.

Pop VJ, Kuijpens JL, van Baar AL, Verkerk G, van Son MM, de Vijlder JJ, Vulsma T, Wiersinga WM, Drexhage HA, Vader HL (1999) Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clin Endocrinol (Oxf) 50:149-155

Reid RE, Kim EM, Page D, O'Mara SM, O'Hare E. Thyroxine replacement in an animal model of congenital hypothyroidism.Physiol Behav. 2007 91(2-3):299-303. Epub 2007 Mar 15.

Rovet, J. F. (2002). Congenital hypothyroidism: an analysis of persisting deficits and associated factors." Child Neuropsychol 8(3): 150-62.

Royland JE, Parker JS, Gilbert ME. 2008a. A genomic analysis of subclinical hypothyroidism in hippocampus and neocortex of the developing rat brain. Journal of neuroendocrinology. Dec;20:1319-1338.

Sharlin DS, Tighe D, Gilbert ME, Zoeller RT (2008) The balance between oligodendrocyte and astrocyte production in major white matter tracts is linearly related to serum total thyroxine. Endocrinology 149:2527-2536.

Willoughby KA, McAndrews MP, Rovet J. Effects of maternal hypothyroidism on offspring hippocampus and memory. Thyroid, 2014;24:576-584.

Zoeller RT, Rovet J. Timing of thyroid hormone action in the developing brain: clinical observations and experimental findings. J Neuroendocrinol. 2004 Oct;16(10):809-18.