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  • br AHR mediates TCDD toxicity and wasting

    2023-01-21


    AHR mediates TCDD toxicity and wasting syndrome TCDD causes numerous toxicities in laboratory animals, including teratogenesis, hepatic steatosis, thymic atrophy, immune dysfunction and a lethal wasting syndrome [17]. The dose-dependent sensitivity to TCDD-induced toxicities varies widely among laboratory species and strains [1]. A single dose of TCDD to mice induces a lethal starvation-like syndrome, which includes decreased gluconeogenesis, hepatotoxicity, hepatosteatosis, body weight loss and lethality [1,17]. Reduced serum glucose levels do not correlate with lethality in all species, and total parental feeding prevents body weight loss but not lethality [17]. Ahr null and Ahr DBDmut mice, which express an AHRE binding deficient mutant of AHR, are resistant to TCDD toxicity [18,19]. Transgenic AHR overexpressing mice develop hepatosteatosis, while Ahr null mice and high fat diet fed mice treated with an AHR antagonist as well as Cyp1b1 deficient mice are protected against obesity and hepatosteatosis [20–22]. This suggests that TCDD toxicity requires the canonical AHR signaling pathway and that AHR has a prominent role in lipid homeostasis. Despite the absolute requirement for AHR, the mechanisms and downstream target genes responsible for these toxic outcomes remain unclear. Male Cyp1a1 deficient mice are protected against wasting syndrome and some, but not all, TCDD-induced toxicity [23]. However, elimination of AHR-dependent regulation of Cyp1a1 through nhs chemical of its upstream AHRE region causes a slight increase in sensitivity to TCDD toxicity [24]. Ahrr null mice exhibit tissue-specific increases in Cyp1a1 levels and reduced sensitivity to benzo[a]pyrene-induced DNA adduct formation in skin [15]. Unfortunately, the sensitivity of Ahrr null mice to acute TCDD toxicity has not been reported; however, transgenic overexpression of Ahrr in mice protects then against high dose TCDD-induced lethality [25].
    TCDD-inducible poly-ADP-ribose polymerase (TIPARP) TIPARP, a relatively uncharacterized AHR target gene, was recently reported to directly regulate AHR activity and mediate cellular responses downstream of AHR [26,27]. TIPARP (PARP7/ARTD14) is a member of the poly ADP-ribose polymerase (PARP) family also called the ADP-ribosyltransferase diphtheria toxin-like (ARTD) family. PARPs catalyze the transfer of ADP-ribose from nicotinamide adenine dinucleotide (NAD+) to specific amino acid residues on themselves and on target proteins releasing nicotinamide (NAM). There are 17 PARPs in humans with the majority nhs chemical of them able to catalyze the transfer of one molecule of ADP-ribose (mono-ADP-ribosylation) rather than several ADP-ribose moieties, (poly-ADP-ribosylation) to target proteins [28,29]. ADP-ribosylation profoundly alters target protein activity and plays a role in numerous cellular stress responses, including DNA repair, oxidative stress, immune responses, but also transcription, protein degradation and metabolism [30,31]. NAD+ is vital for all organisms and a dietary NAD+-deficiency causes pellagra in humans [32]. The increased enzymatic activity of PARP1, which generates poly-ADP-ribose modifications, during extreme DNA damage results in rapid decreases in cellular NAD+ levels leading to increased cell death [33]. Whether activation of mono-ADP-ribosyltransferases is sufficient to reduce cellular NAD+ levels below critical levels is unclear. ADP-ribosylation is dynamically regulated by poly-ADP-ribose glycohydrolase (PARG) and ADP-ribosyl hydrolases (ARHs). Similarly, macrodomain containing proteins, MACROD1, MACROD2, and C6orf130 recognize and hydrolyze mono-ADP-ribose from modified proteins [34,35]. TIPARP was first identified as a TCDD responsive gene in mouse hepatoma cells [11]. It is widely expressed in many tissues and cell lines [11,27]. Both the human and mouse TIPARP genes feature a concatemer of AHRE sequences found in well-characterized AHR target genes [36]. A non-coding TIPARP antisense RNA, which lies upstream of exon 1, is also regulated by the same AHRE sequences, but its biological importance is unknown [36]. In addition, TIPARP is regulated by other transcription factors and signaling pathways, including androgen receptor [37], hypoxia factor 1α [38] platelet derived growth factor [39] and interferons [40], suggesting that this enzyme has vast and divergent cellular roles.