Role of Chaperone Proteins in AHR Function

Murray, Iain A.; Perdew, Gary H.

doi:10.1002/9781118140574.ch3

Cited by 5 publications

(5 citation statements)

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“…In Figure , the canonical AHR signalling pathway is depicted with solid black arrows. In its inactive state, AHR resides in the cytosol in a protein complex comprising a dimer of HSP90 and the co‐chaperones AIP (also known as XAP2) and p23 (Murray and Perdew et al., ). TCDD penetrates the cell membrane by diffusion.…”

Section: Assessmentmentioning

confidence: 99%

Risk for animal and human health related to the presence of dioxins and dioxin‐like PCBs in feed and food

Knutsen¹,

Alexander²,

Barregård³

et al. 2018

EFS2

137

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The European Commission asked EFSA for a scientific opinion on the risks for animal and human health related to the presence of dioxins (PCDD/Fs) and DL‐PCBs in feed and food. The data from experimental animal and epidemiological studies were reviewed and it was decided to base the human risk assessment on effects observed in humans and to use animal data as supportive evidence. The critical effect was on semen quality, following pre‐ and postnatal exposure. The critical study showed a NOAEL of 7.0 pg WHO2005‐TEQ/g fat in blood sampled at age 9 years based on PCDD/F‐TEQs. No association was observed when including DL‐PCB‐TEQs. Using toxicokinetic modelling and taking into account the exposure from breastfeeding and a twofold higher intake during childhood, it was estimated that daily exposure in adolescents and adults should be below 0.25 pg TEQ/kg bw/day. The CONTAM Panel established a TWI of 2 pg TEQ/kg bw/week. With occurrence and consumption data from European countries, the mean and P95 intake of total TEQ by Adolescents, Adults, Elderly and Very Elderly varied between, respectively, 2.1 to 10.5, and 5.3 to 30.4 pg TEQ/kg bw/week, implying a considerable exceedance of the TWI. Toddlers and Other Children showed a higher exposure than older age groups, but this was accounted for when deriving the TWI. Exposure to PCDD/F‐TEQ only was on average 2.4‐ and 2.7‐fold lower for mean and P95 exposure than for total TEQ. PCDD/Fs and DL‐PCBs are transferred to milk and eggs, and accumulate in fatty tissues and liver. Transfer rates and bioconcentration factors were identified for various species. The CONTAM Panel was not able to identify reference values in most farm and companion animals with the exception of NOAELs for mink, chicken and some fish species. The estimated exposure from feed for these species does not imply a risk.

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Section: Assessmentmentioning

confidence: 99%

Risk for animal and human health related to the presence of dioxins and dioxin‐like PCBs in feed and food

Knutsen¹,

Alexander²,

Barregård³

et al. 2018

EFS2

137

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“…The aryl hydrocarbon receptor (AHR), a member of the Per-ARNT-Sim (bHLH/PAS) family of proteins (McIntosh, Hogenesch, & Bradfield, 2010), is a ligand-activated transcription factor that mediates the toxicity of a wide range of environmental contaminants, including chlorinated dioxin-like compounds and polynuclear aromatic hydrocarbons (Denison, Soshilov, He, DeGroot, & Zhao, 2011). The unliganded receptor is part of a cytoplasmic complex with hsp90, p23, and AIP (Murray & Perdew, 2011). Agonist binding triggers translocation to the nucleus, shedding of these chaperones, and dimerization with the ARNT protein.…”

Section: Introductionmentioning

confidence: 99%

An aryl hydrocarbon receptor from the caecilian Gymnopis multiplicata suggests low dioxin affinity in the ancestor of all three amphibian orders

Kazzaz

Tagliabue

Franks

et al. 2020

General and Comparative Endocrinology

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The aryl hydrocarbon receptor (AHR) plays pleiotropic roles in the development and physiology of vertebrates in conjunction with xenobiotic and endogenous ligands. It is best known for mediating the toxic effects of dioxin-like pollutants such as 2,3,7,8tetracholordibenzo-p-dioxin (TCDD). While most vertebrates possess at least one AHR that binds TCDD tightly, amphibian AHRs bind TCDD with very low affinity. Previous analyses of AHRs from Xenopus laevis (a frog; order Anura) and Ambystoma mexicanum (a salamander; order Urodela) identified three amino acid residues in the ligand-binding domain (LBD) that underlie low-affinity binding. In X. laevis AHR1β, these are A354, A370, and N325. Here we extend the analysis of amphibian AHRs to the caecilian Gymnopis multiplicata, representing the remaining extant amphibian order, Apoda. G. multiplicata AHR groups with the monophyletic vertebrate AHR/AHR1 clade.The LBD includes all three signature residues of low TCDD affinity, and a structural homology model suggests that its architecture closely resembles those of other amphibians. In transactivation assays, the EC50 for reporter gene induction by TCDD was 17.17 nM, comparable to X. laevis AhR1β (26.23 nM) and Ambystoma AHR (34.09 nM) and dramatically higher than mouse AhR (0.13 nM), a trend generally reflected in direct measures of TCDD binding. These shared properties distinguish amphibian AHRs from the high-affinity proteins typical of both more ancient vertebrate groups (teleost fish) and those that appeared more recently (tetrapods). We suggest that AHRs with low TCDD affinity represent a basal characteristic that evolved in a common ancestor of all three extant amphibian groups.

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“…These and molecular cloning studies [19,20] have revealed that AHR is a ligand-activated transcription factor which functionally resembles steroid receptors, foremost glucocorticoid receptors, but structurally belongs to a fundamentally different protein superfamily, the bHLH/PAS (basic helix-loop-helix/Periodic-ARNT-Single-minded) proteins. Unliganded AHR resides in the cytosol in a protein complex also comprising a dimer of HSP90 and the co-chaperones AIP (also known as XAP2) and p23 [21]. The chaperones stabilize the AHR, maintain it in an optimal conformation for binding ligand, and inhibit its translocation into the nucleus [21,22,23,24].…”

Section: Introductionmentioning

confidence: 99%

“…Unliganded AHR resides in the cytosol in a protein complex also comprising a dimer of HSP90 and the co-chaperones AIP (also known as XAP2) and p23 [21]. The chaperones stabilize the AHR, maintain it in an optimal conformation for binding ligand, and inhibit its translocation into the nucleus [21,22,23,24]. Binding of TCDD to the AHR causes a transformation in its conformation [25,26], and the protein complex translocates into the nucleus [27].…”

Section: Introductionmentioning

confidence: 99%

Multigenerational and Transgenerational Effects of Dioxins

Viluksela

Pohjanvirta

2019

IJMS

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Dioxins are ubiquitous and persistent environmental contaminants whose background levels are still reason for concern. There is mounting evidence from both epidemiological and experimental studies that paternal exposure to the most potent congener of dioxins, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), can lower the male/female ratio of offspring. Moreover, in laboratory rodents and zebrafish, TCDD exposure of parent animals has been reported to result in reduced reproductive performance along with other adverse effects in subsequent generations, foremost through the paternal but also via the maternal germline. These impacts have been accompanied by epigenetic alterations in placenta and/or sperm cells, including changes in methylation patterns of imprinted genes. Here, we review recent key studies in this field with an attempt to provide an up-to-date picture of the present state of knowledge to the reader. These studies provide biological plausibility for the potential of dioxin exposure at a critical time-window to induce epigenetic alterations across multiple generations and the significance of aryl hydrocarbon receptor (AHR) in mediating these effects. Currently available data do not allow to accurately estimate the human health implications of these findings, although epidemiological evidence on lowered male/female ratio suggests that this effect may take place at realistic human exposure levels.

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Role of Chaperone Proteins in AHR Function

Cited by 5 publications

References 100 publications

Risk for animal and human health related to the presence of dioxins and dioxin‐like PCBs in feed and food

Risk for animal and human health related to the presence of dioxins and dioxin‐like PCBs in feed and food

An aryl hydrocarbon receptor from the caecilian Gymnopis multiplicata suggests low dioxin affinity in the ancestor of all three amphibian orders

Multigenerational and Transgenerational Effects of Dioxins

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