Upstream eventT4 in serum, Decreased
Hippocampal Physiology, 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||Moderate||Low|
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.
Empirical support for this indirect KER is rated as strong. Empirical data from studies that measure serum TH concentrations and then assess alterations in synaptic function in the hippocampus have come from several laboratories. This work has employed in vivo, ex vivo and in vitro preparations from developmentally exposed animals.
Most of the in vivo neurophysiological assessments have been performed in the dentate gyrus. Excitatory and inhibitory synaptic transmission were reduced by PTU in a dose-dependent fashion (Gilbert and Sui, 2006; Gilbert et al., 2007; Gilbert, 2011). Serum T4 decrements in dams and pups were positively correlated with the synaptic impairments. Serum T4 and hippocampal excitatory transmission were also reduced in pups from dams exposed to perchlorate (Gilbert et al., 2008) and iodine deficiency (Gilbert et al., 2013). However, serum T4 reductions induced by the complex PCB mixture, A1254, were associated with increases not decrements in excitatory response amplitudes (Gilbert et al., 2003).
Impaired synaptic transmission and plasticity in the form of long-term potentiation (LTP) and long-term depression (LTD) have been reported using in vitro and ex vivo preparations (Sui and Gilbert, 2003; Sui et al., 2005; 2007; Gilbert and Sui, 2006; Gilbert and Paczkowski, 2003; Gilbert, 2011; Taylor et al., 2008; Vara et al., 2002), Dong et al., 2005; Gilbert, 2003; 2004; 2011; Gilbert et al., 2016; ), .
In many studies these observations have been reported under conditions of severe hypothyroidism induced primarily by TPO-inhibitors MMI and PTU or severe iodine deficiency (Vara et al., 2002; Dong et al., 2005). In others, researchers produced graded degrees of TH insufficiency in dams and pups by administering varying doses of PTU, perchlorate, or dietary iodine deficiency, and reported dose-dependency of the observed effects. This work has provided increased confidence in the relationship between TH insufficiency and functional impairment of the hippocampus, and the specificity of the observed effects to be mediated by TH insufficiency (Gilbert and Sui, 2006; Gilbert, 2011; Gilbert et al., 2013; 2016).
As described in the KER entitled “Hippocampal anatomy, altered leads to Hippocampal Physiology, Altered”, there is dynamic reciprocal interplay between neuroanatomy and physiology, particularly evident in the developing nervous sytem, making it difficult to parse the effects of one independently of the other (Kozorovitsky et al., 2012). In the in vitro studies of Westerholz et al (2010; 2013), T3-induced increase in GABAgeric synapses is activity-dependent, in that the anatomical changes described required both spontaneous electical activity in the network in addition to thyroid hormone. The electrophysiological competence of that emerging synaptic network was similarly dependent upon the hormone stimulation in addition to the growth of the GABAergic neurons. In this manner, TH can directly influence the formation of emerging cortical networks. Although demontrated using cortical neurons, it is expected that very similar processes occur in the developing neural networks of the hippocampus.
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 physiological function in the dentate gyrus (Gilbert 2011; Sanchez-Huerta et al., 2015). Rescue experiments have not been performed in developmental hypothyroid models. In in vitro studies, temporal specificity of the influence of T3 on network activity has been demonstrated (Westerholz et al., 2013).
Dose-Response Evidence: There are several reports on the dose-dependent nature of the correlation between serum THs and changes in hippocampal physiology albeit from a limited number of laboratories (Taylor et al., 2008; Gilbert et al., 2007; 2016; Gilbert 2011; Gilbert and Sui, 2006).
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).
Quantitative Understanding of the Linkage
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.
Gilbert ME. Perinatal exposure to polychlorinated biphenyls alters excitatory synaptic transmission and short-term plasticity in the hippocampus of the adult rat. Neurotoxicology. 2003 Dec;24(6):851-60.
Gilbert ME. Alterations in synaptic transmission and plasticity in area CA1 of adult hippocampus following developmental hypothyroidism. Brain Res Dev 2004 Jan 31;148(1):11-8
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, Hedge JM, Valentín-Blasini L, Blount BC, Kannan K, Tietge J, Zoeller RT, Crofton KM, Jarrett JM, Fisher JW. An animal model of marginal iodine deficiency during development: the thyroid axis and neurodevelopmental outcome. Toxicol Sci. 2013 Mar;132(1):177-95.
Gilbert ME, Paczkowski C. Propylthiouracil (PTU)-induced hypothyroidism in the developing rat impairs synaptic transmission and plasticity in the dentate gyrus of the adult hippocampus. Brain Res Dev Brain Res. 2003 Oct 10;145(1):19-29
Gilbert ME, Sanchez-Huerta K, Wood C. Mild Thyroid Hormone Insufficiency During Development Compromises Activity-Dependent Neuroplasticity in the Hippocampus of Adult Male Rats. Endocrinology. 2016 Feb;157(2):774-87.
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, Sui L. Developmental exposure to perchlorate alters synaptic transmission in hippocampus of the adult rat. Environ Health Perspect. 2008 Jun;116(6):752-60.
Gilbert ME, Sui L, Walker MJ, Anderson W, Thomas S, Smoller SN, Schon JP, Phani S, Goodman JH. Thyroid hormone insufficiency during brain development reduces parvalbumin immunoreactivity and inhibitory function in the hippocampus. Endocrinology. 2007 Jan;148(1):92-102. PubMed PMID: 17008398.
Kozorovitskiy Y, Saunders A, Johnson CA, Lowell BB, Sabatini BL. Recurrent network activity drives striatal synaptogenesis. Nature. 2012 May 13;485(7400):646-50.
Sánchez-Huerta K, Pacheco-Rosado J, Gilbert ME. Adult onset-hypothyroidism: alterations in hippocampal field potentials in the dentate gyrus are largely associated with anaesthesia-induced hypothermia. J Neuroendocrinol. 2015 Jan;27(1):8-19.
Seed J, Carney EW, Corley RA, Crofton KM, DeSesso JM, Foster PM, Kavlock R, Kimmel G, Klaunig J, Meek ME, Preston RJ, Slikker W Jr, Tabacova S, Williams GM, Wiltse J, Zoeller RT, Fenner-Crisp P, Patton DE. Overview: Using mode of action and life stage information to evaluate the human relevance of animal toxicity data. Crit Rev Toxicol. 2005 35:664-72.
Sui L, Anderson WL, Gilbert ME. 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. 2005 May;85(1):647-56.
Sui L, Gilbert ME. Pre- and postnatal propylthiouracil-induced hypothyroidism impairs synaptic transmission and plasticity in area CA1 of the neonatal rat hippocampus. Endocrinology. 2003 Sep;144(9):4195-203.
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. doi: 10.1210/en.2008-0020. PubMed PMID: 18372327.
Vara H, Muñoz-Cuevas J, Colino A. Age-dependent alterations of long-term synaptic plasticityin thyroid-deficient rats. Hippocampus. 2003;13(7):816-25.
Westerholz S, de Lima AD, Voigt T. Thyroid hormone-dependent development of early cortical networks: temporal specificity and the contribution of trkB and mTOR pathways. Front Cell Neurosci. 2013 Aug 6;7:121.
Westerholz S, de Lima AD, Voigt T. Regulation of early spontaneous network activity and GABAergic neurons development by thyroid hormone. Neuroscience. 2010Jun 30;168(2):573-89.