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AhR activation in the liver leading to Subsequent Adverse Neurodevelopmental Outcomes in Mammals
Point of Contact
- Prakash Patel
- Simon Thomas
|Handbook Version||OECD status||OECD project|
This AOP was last modified on June 02, 2023 17:45
Revision dates for related pages
|Activation, AhR||December 20, 2022 08:29|
|Induction, Upregulation of glucuronyltransferase activity||September 16, 2017 10:14|
|Increased, Clearance of thyroxine from serum||January 26, 2021 10:41|
|Thyroxine (T4) in serum, Decreased||October 10, 2022 08:52|
|Thyroxine (T4) in neuronal tissue, Decreased||April 04, 2019 09:13|
|Hippocampal gene expression, Altered||August 11, 2018 09:26|
|Hippocampal Physiology, Altered||August 11, 2018 09:41|
|Cognitive Function, Decreased||August 09, 2018 11:55|
|Activation, AhR leads to Induction, Upregulation of glucuronyltransferase activity||April 12, 2023 11:25|
|T4 in serum, Decreased leads to Cognitive Function, Decreased||August 11, 2018 19:44|
|Induction, Upregulation of glucuronyltransferase activity leads to Increased, Clearance of thyroxine from serum||September 10, 2021 08:32|
|Increased, Clearance of thyroxine from serum leads to T4 in serum, Decreased||January 26, 2021 10:42|
|T4 in serum, Decreased leads to T4 in neuronal tissue, Decreased||April 04, 2019 10:50|
|T4 in neuronal tissue, Decreased leads to Hippocampal gene expression, Altered||August 11, 2018 19:18|
|Hippocampal gene expression, Altered leads to Hippocampal Physiology, Altered||April 12, 2023 11:28|
|Hippocampal Physiology, Altered leads to Cognitive Function, Decreased||August 11, 2018 19:24|
|2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)||February 09, 2017 14:32|
|Polychlorinated biphenyl||November 29, 2016 18:42|
|PCB 126||April 20, 2023 20:20|
Polychlorinated biphenyls (PCBs) and dioxins are environmental contaminatants whose prenatal exposure in humans and exposure in breast milk is correlated to a specific set of mental impairments (Boucher et al. 2009, Boersma and Lanting 2000, Koopman-Esseboom et al. 1996). What the main mechanism(s) of causing these delays for the various PCBs and dioxins is unclear, but studies in rodents regarding 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) and "dioxin-like" PCBs like PCB-126 that it could be caused by lowering maternal and subsequently foetal thyroxine (T4) levels in the brain.
This AOP summarises the findings that chemicals that are AhR receptor agonists can reduce T4 levels in the plasma in rodents and possibly humans and lead to brain changes in neonates, via activation of liver enzymes that increase the metabolism of T4.
This AOP was created in order to collate and summarise information around the reduction of T4 levels in the plasma by endocrine disruptors, distinct from the reduction of binding to plasma proteins or interfering with thyroid hormone secretion. A short summary:
- Chemical activates AhR
- UGT activity in the liver increases
- More T4 is metabolised and reduces plasma T4 levels
- Adverse outcomes (such as cognitive impairment)
The problem is that AhR agonists TCDD and dioxin-like PCBs (PCB-126, PCB-169) have multiple effects on several organs as AhR receptor is present in these organs whose influence cannot be ruled out (complementary to AOP 459: AhR activation in the thyroid leading to Subsequent Adverse Neurodevelopmental Outcomes in Mammals) but its effect on the liver has been relatively well-characterised.
Also, one needs to understand that all AhR agonists do not produce toxic effects - some are found in vegetables, fruits and teas and are important for normal physiology. AhR -/- mice develop immune and liver defects (Quintana 2012). For the case of 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) which is a potent agonist of AhR in vitro and in vivo but does not cause toxic effects (Henry et al. 2006)
AOP Development Strategy
This AOP was developed as part of the ScreenED project, which has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 825745
This AOP summarises the findings of Kohn et al. 1996 and other papers that corroborate its findings, whilst also summarising evidence of hippocampal and mental effects on rodents of TCDD and various PCBs, although their effects on the thyroid directly and other organs cannot be ruled out. Relevant publications were found by searching through PubMed for terms such as "AhR" "thyroxine" "TCDD" "T4".
Summary of the AOP
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
|Type||Event ID||Title||Short name|
|MIE||18||Activation, AhR||Activation, AhR|
|KE||295||Induction, Upregulation of glucuronyltransferase activity||Induction, Upregulation of glucuronyltransferase activity|
|KE||961||Increased, Clearance of thyroxine from serum||Increased, Clearance of thyroxine from serum|
|KE||281||Thyroxine (T4) in serum, Decreased||T4 in serum, Decreased|
|KE||280||Thyroxine (T4) in neuronal tissue, Decreased||T4 in neuronal tissue, Decreased|
|KE||756||Hippocampal gene expression, Altered||Hippocampal gene expression, Altered|
|KE||758||Hippocampal Physiology, Altered||Hippocampal Physiology, Altered|
|AO||402||Cognitive Function, Decreased||Cognitive Function, Decreased|
Relationships Between Two Key Events (Including MIEs and AOs)
|Activation, AhR leads to Induction, Upregulation of glucuronyltransferase activity||adjacent||High||High|
|Induction, Upregulation of glucuronyltransferase activity leads to Increased, Clearance of thyroxine from serum||adjacent||High||High|
|Increased, Clearance of thyroxine from serum leads to T4 in serum, Decreased||adjacent||High||High|
|T4 in serum, Decreased leads to T4 in neuronal tissue, Decreased||adjacent||High||Moderate|
|T4 in neuronal tissue, Decreased leads to Hippocampal gene expression, Altered||adjacent||High||Moderate|
|Hippocampal gene expression, Altered leads to Hippocampal Physiology, Altered||adjacent||Moderate||Low|
|Hippocampal Physiology, Altered leads to Cognitive Function, Decreased||adjacent||Low||Low|
|T4 in serum, Decreased leads to Cognitive Function, Decreased||non-adjacent||High||High|
Life Stage Applicability
|Birth to < 1 month||Moderate|
Overall Assessment of the AOP
Domain of Applicability
Domain of Applicability
- Chemicals: This AOP applies to a wide range of chemicals structures that activate AhR either in vivo or in vitro, but one needs to understand that not all AhR agonists do not produce toxic effects
- Sex: This AOP applies to males and females. Disruption of thyroid hormone regulation during foetal and early postnatal development, but the subsequent adverse impacts on nervous system development may differ and be more severe in males than females (Seo et al. 1999, Rice 1999).
- Life stages: The relevant life stages for this AOP are fetal and early postnatal ages during critical windows of nervous system development where thyroid hormones guide normal development of the brain. There are clear windows of developmental susceptibility and different brain regions show distinct ontogenetic profiles for TH requirements. Distinct phenotypes have been described in both humans and animal models for different periods of TH insufficiency. The influence of maternal thyroid status prior to onset of fetal thyroid function is an important consideration. This AOP does not apply to adult life states.
- Taxonomic: Based on the majority of the available evidence the taxonomic applicability domains of this AOP is mammals. Most evidence for this AOP has been gathered primarily from laboratory rodents and humans.
Essentiality of the Key Events
No or contradictory evidence
TCDD and various PCBs can be confirmed to be agonists of AhR from both the EROD (Petrulis et al. 1999) and CALUX assay (Murk et al. 1996) to estimate exposure and activation of the AhR-ARNT pathways.
TCDD – upregulation of UGT1A6 in mouse pups heterozygous for AhR +/- gene but not for AhR -/- gene whose mothers were administered 10 ug/kg TCDD on gestation day 12.5 (Nishimura et al. 2005)
Induction of the UGT-1 gene in Holtzman rats (TCDD-sensitive strain) in pups whose mothers were given a single oral dose of 200 ng or 800 ng TCDD/kg on gestational day 15 (Nishimura et al. 2003)
TCDD - liver UGT mRNA increased in female Sprague-Dawley rats compared to controls after a TCDD dose of 3.5 and 100 ng/kg/day for 31 weeks (Sewall et al. 1995)
PCB-126 - increase in T4-glucuronide production in adult male SD rats compared to controls (Fisher et al. 2006)
TCDD - rats cleared more T4 via the biliary route (Bastomsky 1977) and more T4-glucuronide excreted (Bastomsky 1977, Henry and Gasiewicz 1987)
TCDD – reduction of serum T4 in pups heterozygous for AhR +/- gene but not for AhR -/- gene whose mothers were administered 10 ug/kg TCDD on gestation day 12.5 (Nishimura et al. 2005)
Reduction in serum T4 in Holtzman rats (TCDD-sensitive strain) in pups whose mothers were given a single oral dose of 200 ng or 800 ng TCDD/kg on gestational day 15 (Nishimura et al. 2003)
PCB-126: Pregnant albino rats received PCB 126 (20 or 40μg/kgb.wt.) by oral gavage from gestation day (GD) 1 to 20. Both administrations of PCB 126 elevated serum thyrotropin (TSH) concentration, and decreased free thyroxine (FT4) and free triiodothyronine (FT3) concentrations, resulting in a maternofetal hypothyroidism (Ahmed et al. 2018).
Arochlor 1254 - SD rat dams were dosed daily with 0, 1, or 4 mg/kg A1254 from gestational day 6 (GD6) until they were sacrificed on GD16. A1254 significantly reduced circulating levels of triiodothyronine(T3) and thyroxine (T4) in pregnant rats (Gauger et al. 2004)
TCDD - Marked dose-dependent reduction in T4 recorded in rats (Kohn et al. 1996, National Toxicology Program 2006)
PCB-126 - reductions in serum T4 on acute (Fisher et al. 2006) and chronic administration of PCB-126 (National Toxicology Program 2006)
Several studies have demonstrated that fetal brain TH levels, previously decreased by maternal exposure to TH synthesis inhibitors or thyroidectomy, recovered following maternal supply of T4 (e.g., Calvo et al., 1990). However, there are no studies with direct infusion of T4 or T3 directly into brain.
The upregulation of deiodinase has been shown to compensate for some loss of neuronal T3 (Escobar-Morreale et al. 1995; Escobar-Morreale et al. 1997).
Indirect evidence shows that T4 replacement that brings circulating T4 concentration back to physiological levels normal, leads to recovery of brain TH and prevents downstream effects including alterations in cell morphology, differentiation and function.
PCB-118 acted via the TH pathway in the rat foetus whilst PCB-126 did not and acted mainly via reducing maternal thyroid hormone levels (Fritsche et al. 2005, Gauger et al. 2004)
Hippocampal Gene Expression, Altered: It is well established specific genomic pathways underlie the progression of a number of neurodevelopmental processes in the hippocampus. There is some evidence from ex vivo studies that administration of growth factors will reverse the hippocampal dysplasia seen in Jacob/Nsfm knockout mice (Spilker et al., 2016). Less is known about the impact of hormone replacement on TH-responsive gene expression and the qualitative and quantitative relationships between altered TH-dependent gene expression in this brain region and altered hippocampal cytoarchitectural anatomy.
Hippocampal anatomy, altered: It is well accepted that normal hippocampal anatomy is critical for hippocampal physiological function, and that alterations in anatomy lead to altered neuronal activity in the hippocampus (Lee et al., 2015; Grant et al., 1992; Spilker et al., 2016).
Hippocampal physiology, altered: It is a well-accepted assertion that hippocampal synaptic integrity and neuronal plasticity are essential for spatial information processing in animals and spatial and episodic memory in humans. However, other brain regions also can influence these complex behaviors. Limited data from studies in BDNF knockout animals demonstrate that deficits in hippocampal synaptic transmission and plasticity, and downstream behaviors can be rescued with recombinant BDNF (Aarse et al. 2016; Andero et al. 2014).
The relative size of the IIP-MF in females and males. The IIP-MF was smaller in TCDD exposed female AhR+/- mice with respect to their genotype control group. (Powers et al. 2005)
Pregnant Sprague-Dawley rats were given a consecutive daily dose of TCDD (200 or 800 ng/day/kg) or an equivalent volume of vehicle by gavage on gestational days 8-14 as the prenatal TCDD exposure model. When the male pups grew to adults, morphology and number of neurons in the hippocampus CA1 region was not affected, although the activity of astrocytes in the same region was significantly reduced (Zhang et al. 2018)
TCDD exposed female AhR+/- mice performed worse on the spatial water maze task than non exposed mice (Powers et al. 2005)
Pregnant Sprague-Dawley rats were given a consecutive daily dose of TCDD (200 or 800 ng/day/kg) or an equivalent volume of vehicle by gavage on gestational days 8-14. The results of the behavioural tests showed that gestational TCDD exposure induced premature motor activity and earlier eyes-opening, but lead to serious deficits of spatial memory and learning ability in adult male offspring. (Zhang et al 2018)
Monkeys exposed to TCDD perinatally exhibited retarded learning of shape reversals (Shantz and Bowman 1994)
Pregnant Long-Evans rats were dosed by gavage with TCDD or at a dose of 0, 200, or 800 ng/kg on gestational day 15, and the offspring was tested during adulthood. Paired-associate learning was found to be impaired in the 200 ng/kg TCDD group, but not in either group exposed to 800 ng/kg TCDD (Kakeyama et al. 2014)
Long-Evans dams dosed at 0, 0.25, or 1.0 ug/kg/day PCB-126 Monday to Friday beginning 5 weeks before and continuing through gestation and lactation. On the spatial delayed alternation task, there was no convincing evidence for impairment as a result of PCB exposure on adult male pups, as assessed by overall accuracy of performance and measures of perseverative and other types of inappropriate responding. (Rice 1999)
Time-mated Sprague–Dawley rats were gavaged with either TCDD (0.1 ug/kg/day) or corn oil vehicle on gestation days 10–16. On day 80, both male and female TCDD-exposed grown-up pups showed a deficit in learning on the visual partial discrimination-reversal learning task, but TCDD-exposed male rats displayed a pronounced decrease in errors relative to control males in the Morris Water Maze task. There was no difference in the performance of TCDD exposed rats in the radial arm maze task. (Seo et al. 1999)
Pregnant Sprague–Dawley rats (10 per dose) received either 0 or 0.1 ug/kg TCDD orally in corn oil from GD 10 to GD 16. One male and one female from each litter were tested beginning at 100 days of age. the results of the current study underscore the fact that (1) alterations in cognitive function observed following early TCDD exposure are very subtle and (2) under some conditions, learning is actually facilitated, rather than impaired, in TCDD-exposed animals. (Widholm et al. 2003)
Monkeys exposed to TCDD perinatally showed a slight facilitation of learning on both delayed spatial alternation and spatial reversal learning tasks (Seegal and Schantz 1994)
Biological plausibility refers to the structural or functional relationship between the key events based on our fundamental understanding of "normal biology".
In general, the biological plausibility and coherence linking AhR activation by PCBs and dioxins to decreases in circulating concentrations of THs is great. The biological plausibility of decreases in circulating concentrations of THs, to adverse impacts in the developing hippocampus and subsequent cognitive behaviors is very solid (AOP 42). The problem is the interaction with PCBs and dioxins directly with the foetal brain can act like thyroid hormones due to its similar shape to these compounds, and may compensate for the reduction of THs there. Some of the adverse effects have more in common with congenital hyperthyroidism than hypothyroidism e.g. that gestational TCDD exposure induced premature motor activity in neonatal rats and earlier eyes-opening (Zhang et al. 2018).
Concordance of dose-response relationships:
There are several studies that include correlative evidence between exposure to AhR agonists TCDD (Kohn et al. 1996, NTP 2006) and PCB-126 (NTP, 2006) to downstream KEs up until the reduction of T4 in the plasma (KE 281). Referring to the AOPs 42 and 54, there is ample evidence the reduction of plasma T4 correlates to neurological deficits. What is unclear is the effect of dioxin or dioxin-like PCB effects directly on the brain itself which can activate the TH receptors mitigate the effects of low T4 (Gauger et al. 2004, Fritsche et al. 2005, Kitamura et al. 2005, Zhang et al. 2018), so the dose concordance is still unproven due to this.
Temporal concordance among the key events and adverse effect:
There are two aspects of the temporal concordance of the key events in a developmental AOP. The first is the temporal concordance refers to the degree to which the data support the hypothesized sequence of the key events; i.e., the effect on KE1 is observed before the effect on KE2, which is observed before the effect on KE3, and so on. This translates to the temporal concordance of the AOP from AhR activation to decreased TH synthesis, reduced circulating TH concentrations, decreased nervous system TH, altered gene expression and anatomy in the hippocampus, and subsequent alterations in hippocampal physiology that result in decrements in cognition. The strength of the temporal concordance between these KEs varies from weak to strong. There is strong evidence for the early direct KEs from both empirical and modelling studies, and for many of the later KEs via the indirect KERs. The temporal concordance between AhR activation and TH synthesis is clearly evidenced by data from ex vivo and in vitro studies, as well as computational models (Kohn et al. 1996). Data supporting the temporal concordance for the later KEs, i.e., from serum TH to changes in hippocampal physiology are limited or lacking.
The second aspect of temporal concordance for developmental AOPs is evidenced by demonstrations for critical windows of development where key events are perturbed, for which the effects are permanent and found during early development and throughout adulthood. It is a well-recognized fact that there are critical developmental windows for disruption of serum THs that result in subsequent alterations in all downstream KEs including the AO cognitive function later in development and adulthood.
Uncertainties, inconsistencies, and data gaps:
There are several areas of uncertainty and data gaps in the current AOP, especially regarding the later KERs and AOs. The main uncertainty is that AhR agonists do not produce toxic effects and can’t be measured without in vivo testing. Also, hippocampal changes and effect on mental functions in mammals are hard to measure.
Known Modulating Factors
|Modulating Factor (MF)||Influence or Outcome||KER(s) involved|
|TCDD||May act as agonists to thyroid receptors in the brain to mitigate lower T4 levels (Seo et al. 1999, Widholm et al. 2003)||
|PCB-118||May act as agonists to thyroid receptors in the brain to mitigate lower T4 levels (Gauger et al. 2007)||KER 761|
Assessment of quantitative understanding of the AOP:
Currently, there are quantitative models for the early KERs from AhR activation to serum hormone concentrations (Kohn et al. 1996), but none for later KERs. One could link the reduction of thyroid hormones to malformations in the brain, as in Hassan et al. (2017) quantitatively linked PTU-induced TH synthesis declines in the dam and the foetus to decrements in serum and brain TH concentrations to a structural malformation in the postnatal brain. At present, the overall quantitative understanding of the AOP is insufficient to directly link a measure of chemical potency as a TPO inhibitor to a quantitative prediction of effect on cognitive function (e.g., IQ in humans, learning deficits in rodents).
Considerations for Potential Applications of the AOP (optional)
To determine whether a particular compound can potentially cause this AO, one must find out first if the compound is a activator of UGT isoforms in the liver that can glucuronidate T4. It is not sufficient to see whether it has a positive outcome from the EROD or CALUX assays as they only measure CYP inhibition and AhR nuclear activation, respectively.
This could possibly done in hepatocyte cell lines or primary hepatocytes, but it is uncertain what level of activation would cause T4 levels to go sufficiently down in the brain in vivo to counteract that some AhR agonists can also activate thyroid hormone receptors in the brain and can mitigate the AO.
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