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Relationship: 384

Title

The title of the KER should clearly define the two KEs being considered and the sequential relationship between them (i.e., which is upstream and which is downstream). Consequently all KER titles take the form “upstream KE leads to downstream KE”.  More help

Altered, Neurophysiology leads to Cognitive Function, Decreased

Upstream event
Upstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help
Downstream event
Downstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help

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

This table is automatically generated upon addition of a KER to an AOP. All of the AOPs that are linked to this KER will automatically be listed in this subsection. Clicking on the name of the AOP in the table will bring you to the individual page for that AOP. More help
AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
XX Inhibition of Sodium Iodide Symporter and Subsequent Adverse Neurodevelopmental Outcomes in Mammals adjacent Moderate Low Kevin Crofton (send email) Not under active development

Taxonomic Applicability

Select one or more structured terms 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. Authors can indicate the relevant taxa for this KER in this subsection. The process is similar to what is described for KEs (see pages 30-31 and 37-38 of User Handbook) More help

Sex Applicability

Authors can indicate the relevant sex for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of the User Handbook). More help

Life Stage Applicability

Authors can indicate the relevant life stage for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of User Handbook). More help

Key Event Relationship Description

Provide a brief, descriptive summation of the KER. While the title itself is fairly descriptive, this section can provide details that aren’t inherent in the description of the KEs themselves (see page 39 of the User Handbook). This description section can be viewed as providing the increased specificity in the nature of upstream perturbation (KEupstream) that leads to a particular downstream perturbation (KEdownstream), while allowing the KE descriptions to remain generalised so they can be linked to different AOPs. The description is also intended to provide a concise overview for readers who may want a brief summation, without needing to read through the detailed support for the relationship (covered below). Careful attention should be taken to avoid reference to other KEs that are not part of this KER, other KERs or other AOPs. This will ensure that the KER is modular and can be used by other AOPs. More help

Cognitive function and impairments thereof are measured using behavioral techniques. It is well accepted that these alterations in behavior are the result of structural or functional changes in neurocircuitry. Functional impairments are often measured using field potentials of critical synaptic circuits in hippocampus and cortex. A number of studies have been performed in rodent models that reveal deficits in both excitatory and inhibitory synaptic transmission in the hippocampus as a result of developmental thyroid insufficiency.

A well established model of memory at the synaptic levels is known as long-term potentiation (LTP). Deficiencies in LTP are generally regarded as potential substrates of learning and memory impairments.

Evidence Supporting this KER

Assembly and description of the scientific evidence supporting KERs in an AOP is an important step in the AOP development process that sets the stage for overall assessment of the AOP (see pages 49-56 of the User Handbook). To do this, biological plausibility, empirical support, and the current quantitative understanding of the KER are evaluated with regard to the predictive relationships/associations between defined pairs of KEs as a basis for considering WoE (page 55 of User Handbook). In addition, uncertainties and inconsistencies are considered. More help

A number of studies have consistently reported alterations in synaptic transmission resulting from developmental TH disruption and impairments in behavioral tasks assessing learning and memory. It is not clear if all behavioral impairments reported can be directly tied to synaptic dysfunction in the brain regions within which neurotransmission deficits have been recorded. It is not unreasonable to posit that the mechanisms of supporting synaptic transmission and synaptic strengthening are similar in different regions of the brain that support learning and memory and that demonstration at one site where it is most readily assessed implicates this mechanism may also be impaired at other sites as well.

Biological Plausibility
Define, in free text, the biological rationale for a connection between KEupstream and KEdownstream. What are the structural or functional relationships between the KEs? For example, there is a functional relationship between an enzyme’s activity and the product of a reaction it catalyses. Supporting references should be included. However, it is recognised that there may be cases where the biological relationship between two KEs is very well established, to the extent that it is widely accepted and consistently supported by so much literature that it is unnecessary and impractical to cite the relevant primary literature. Citation of review articles or other secondary sources, like text books, may be reasonable in such cases. The primary intent is to provide scientifically credible support for the structural and/or functional relationship between the pair of KEs if one is known. The description of biological plausibility 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 (see page 40 of the User Handbook for further information).   More help

It is well accepted that alterations in synaptic transmission and plasticity contribute to deficits in cognitive function. There are a few studies that have linked exposure to TPO inhibitors (e.g., PTU, MMI) and well as iodine deficient diets, to changes in serum TH levels and have measured both alterations in both synaptic function and cognitive behaviors (Opazo et al., 2009; Dong et al., 2005; Gilbert, 2011; Gilbert and Sui, 2006).

Uncertainties and Inconsistencies
In addition to outlining the evidence supporting a particular linkage, it is also important to identify inconsistencies or uncertainties in the relationship. Additionally, while there are expected patterns of concordance that support a causal linkage between the KEs in the pair, it is also helpful to identify experimental details that may explain apparent deviations from the expected patterns of concordance. Identification of uncertainties and inconsistencies contribute to evaluation of the overall WoE supporting the AOPs that contain a given KER and to the identification of research gaps that warrant investigation (seep pages 41-42 of the User Handbook).Given that AOPs are intended to support regulatory applications, AOP developers should focus on those inconsistencies or gaps that would have a direct bearing or impact on the confidence in the KER and its use as a basis for inference or extrapolation in a regulatory setting. Uncertainties that may be of academic interest but would have little impact on regulatory application don’t need to be described. In general, this section details evidence that may raise questions regarding the overall validity and predictive utility of the KER (including consideration of both biological plausibility and empirical support). It also contributes along with several other elements to the overall evaluation of the WoE for the KER (see Section 4 of the User Handbook).  More help

The direct relationship of alterations in synaptic function and specific cognitive deficits is difficult to ascertain given the many forms that learning and memory can take and the complexity of synaptic interactions in even the simplest brain circuit. Linking of neurophysiological assessments to learning and memory processes have, by necessity, been made across simple monosynaptic connections and largely focused on the hippocampus. Alterations in synaptic function, however, have been found in the absence of behavioral impairments (e.g., Gilbert et al., 2013; 2007). This may result from: 1) Measuring only one component in the complex brain circuitry that underlies 'cognition' 2) Behavioral tests typically used in large dose-response studies allow for processing of large numbers of animals and may not be sufficiently sensitive to detect subtle cognitive impairments 3) Behavioral tasks may be solved by a number of differnt strategies - animals develop alernative strategies as a consequence of developmental insult to compensate for impaired ability.

Response-response Relationship
This subsection should be used to define sources of data that define the response-response relationships between the KEs. In particular, information regarding the general form of the relationship (e.g., linear, exponential, sigmoidal, threshold, etc.) should be captured if possible. If there are specific mathematical functions or computational models relevant to the KER in question that have been defined, those should also be cited and/or described where possible, along with information concerning the approximate range of certainty with which the state of the KEdownstream can be predicted based on the measured state of the KEupstream (i.e., can it be predicted within a factor of two, or within three orders of magnitude?). For example, a regression equation may reasonably describe the response-response relationship between the two KERs, but that relationship may have only been validated/tested in a single species under steady state exposure conditions. Those types of details would be useful to capture.  More help
Time-scale
This sub-section should be used to provide 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?). This can be useful information both in terms of modelling the KER, as well as for analyzing the critical or dominant paths through an AOP network (e.g., identification of an AO that could kill an organism in a matter of hours will generally be of higher priority than other potential AOs that take weeks or months to develop). Identification of time-scale can also aid the assessment of temporal concordance. For example, for a KER that operates on a time-scale of days, measurement of both KEs after just hours of exposure in a short-term experiment could lead to incorrect conclusions regarding dose-response or temporal concordance if the time-scale of the upstream to downstream transition was not considered. More help
Known modulating factors
This sub-section presents information regarding modulating factors/variables known to alter the shape of the response-response function that describes the quantitative relationship between the two KEs (for example, an iodine deficient diet causes a significant increase in the slope of the relationship; a particular genotype doubles the sensitivity of KEdownstream to changes in KEupstream). Information on these known modulating factors should be listed in this subsection, along with relevant information regarding the manner in which the modulating factor can be expected to alter the relationship (if known). Note, this section should focus on those modulating factors for which solid evidence supported by relevant data and literature is available. It should NOT list all possible/plausible modulating factors. In this regard, it is useful to bear in mind that many risk assessments conducted through conventional apical guideline testing-based approaches generally consider few if any modulating factors. More help
Known Feedforward/Feedback loops influencing this KER
This subsection should define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits? In some cases where feedback processes are measurable and causally linked to the outcome, they should be represented as KEs. However, in most cases these features are expected to predominantly influence the shape of the response-response, time-course, behaviours between selected KEs. For example, if a feedback loop acts as compensatory mechanism that aims to restore homeostasis following initial perturbation of a KE, the feedback loop will directly shape the response-response relationship between the KERs. Given interest in formally identifying these positive or negative feedback, it is recommended that a graphical annotation (page 44) indicating a positive or negative feedback loop is involved in a particular upstream to downstream KE transition (KER) be added to the graphical representation, and that details be provided in this subsection of the KER description (see pages 44-45 of the User Handbook).  More help

Domain of Applicability

As for the KEs, there is also a free-text section of the KER description that the developer can use to explain his/her rationale for the structured terms selected with regard to taxonomic, life stage, or sex applicability, or provide a more generalizable or nuanced description of the applicability domain than may be feasible using standardized terms. More help

Synaptic transmission and plasticity are acheived via mechanisms common across taxonomies. LTP has been recorded in aplysia, lizards, turtles, birds, mice, guinea pigs, rabbits and rats.

References

List of the literature that was cited for this KER description using the appropriate format. Ideally, the list of references should conform, to the extent possible, with the OECD Style Guide (OECD, 2015). More help

These references need to be checked. Section on acute effects T3 on LTP and PPF in adult also needs to be added to text above.

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.

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

Berbel P, et al. Distribution of parvalbumin immunoreactivity in the neocortex of hypothyroid adult rats. Neurosci Lett 1996, 204(1-2), 65-68.

Brosvic, G. M., J. N. Taylor, et al. (2002). "Influences of early thyroid hormone manipulations: delays in pup motor and exploratory behavior are evident in adult operant performance." Physiol Behav 75(5): 697-715.

Darbra, S., F. Balada, et al. (2004). "Perinatal hypothyroidism effects on step-through passive avoidance task in rats." Physiol Behav 82(2-3): 497-501.

Darbra, S., A. Garau, et al. (2003). "Perinatal hypothyroidism effects on neuromotor competence, novelty-directed exploratory and anxiety-related behaviour and learning in rats." Behav Brain Res 143(2): 209-15.

Davenport, J. W. and T. P. Dorcey (1972). Hypothyroidism: learning deficit induced in rats by early exposure to thiouracil. Horm Behav 3(2): 97-112.

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

Dong, J., Yin, H., Liu, W., Wang, P., Jiang, Y., and Chen, J. (2005). Congenital iodine deficiency and hypothyroidism impair LTP and decrease C-fos and C-jun expression in rat hippocampus. Neurotoxicology 26, 417–426.

Gilbert ME, Rovet J, Chen Z, Koibuchi N. Developmental thyroid hormone disruption: Prevalence, environmental contaminants and neurodevelopmental consequences. Neurotoxicology. 2012;33(4):842-852.

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, et al. Thyroid hormone insufficiency during brain development reduces parvalbumin immunoreactivity and inhibitory function in the hippocampus. Endocrinology 2007, 148(1), 92-102.

Gilbert, M. E., and Sui, L. (2008). Developmental exposure to perchlorate alters synaptic transmission in hippocampus of the adult rat. Environ. Health Perspect. 116, 752–760.

Koibuchi N, Chin WW. Thyroid hormone action and brain development. Trends Endocrinol Metab 2000, 11(4), 123-128.

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, M. C., Gianini, A., Pancetti, F., Azkcona, G., Alarco´n, L., Lizana, R.,Noches, V., Gonzalez, P. A., Marassi, M. P., Mora, S., et al. (2008). Maternal hypothyroxinemia impairs spatial learning and synaptic nature and function in the offspring. Endocrinology 149, 5097–5106.

Sui, L., W. L. Anderson, et al. (2005). "Impairment in short-term but enhanced long-term synaptic potentiation and ERK activation in adult hippocampal area CA1 following developmental thyroid hormone insufficiency." Toxicol Sci 85(1): 647-56.

Sui, L. and M. E. Gilbert (2003). "Pre- and postnatal propylthiouracil-induced hypothyroidism impairs synaptic transmission and plasticity in area CA1 of the neonatal rat hippocampus." Endocrinology 144(9): 4195-203.

Sui, L., F. Wang, et al. (2006). "Adult-onset hypothyroidism impairs paired-pulse facilitation and long-term potentiation of the rat dorsal hippocampo-medial prefrontal cortex pathway in vivo." Brain Res 1096(1): 53-60.

Sui, L., F. Wang, et al. (2006). "Dorsal hippocampal administration of triiodothyronine enhances long-term memory for trace cued and delay contextual fear conditioning in rats. J Neuroendocrinol 18(11): 811-9.

Insert non-formatted text hereSchalock, R. L., W. J. Brown, et al. (1979). "Long-term effects of propylthiouracil-induced neonatal hypothyroidism." Dev Psychobiol 12(3): 187-99.

Sui, L., F. Wang, et al. (2006). "Dorsal hippocampal administration of triiodothyronine enhances long-term memory for trace cued and delay contextual fear conditioning in rats." J Neuroendocrinol 18(11): 811-9.

Tamasy, V., E. Meisami, et al. (1986). Rehabilitation from neonatal hypothyroidism: spontaneous motor activity, exploratory behavior, avoidance learning and responses of pituitary-thyroid axis to stress in male rats. Psychoneuroendocrinology 11(1): 91-103.

Taylor MA, Swant J, Wagner JJ, Fisher JW, Ferguson DC. Lower thyroid compensatory reserve of rat pups after maternal hypothyroidism: correlation of thyroid, hepatic, and cerebrocortical biomarkers with hippocampal neurophysiology. Endocrinology. 2008 Jul;149(7):3521-30.

Vara H, et al. Thyroid hormone regulates neurotransmitter release in neonatal rat hippocampus. Neuroscience 2002, 110(1), 19-28.

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

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