Obesity II: Establishing causal links between chemical exposures and obesity

Biochemical Pharmacology, Journal Year: 2022, Volume and Issue: 199, P. 115015 - 115015

Published: April 5, 2022

Language: Английский

---

Functions of the aryl hydrocarbon receptor (AHR) beyond the canonical AHR/ARNT signaling pathway

Biochemical Pharmacology, Journal Year: 2022, Volume and Issue: 208, P. 115371 - 115371

Published: Dec. 15, 2022

Language: Английский

---

Mechanisms of Environmental Contributions to Fatty Liver Disease

Current Environmental Health Reports, Journal Year: 2019, Volume and Issue: 6(3), P. 80 - 94

Published: May 27, 2019

Language: Английский

---

Polychlorinated biphenyl exposures differentially regulate hepatic metabolism and pancreatic function: Implications for nonalcoholic steatohepatitis and diabetes

Toxicology and Applied Pharmacology, Journal Year: 2018, Volume and Issue: 363, P. 22 - 33

Published: Oct. 9, 2018

Language: Английский

---

Mechanisms of action of agrochemicals acting as endocrine disrupting chemicals

Molecular and Cellular Endocrinology, Journal Year: 2019, Volume and Issue: 502, P. 110680 - 110680

Published: Dec. 12, 2019

Language: Английский

---

Polychlorinated biphenyls and nonalcoholic fatty liver disease

Current Opinion in Toxicology, Journal Year: 2019, Volume and Issue: 14, P. 21 - 28

Published: April 1, 2019

Language: Английский

---

Nuclear receptor phosphorylation in xenobiotic signal transduction

Journal of Biological Chemistry, Journal Year: 2020, Volume and Issue: 295(45), P. 15210 - 15225

Published: Aug. 11, 2020

Nuclear pregnane X receptor (PXR, NR1I2) and constitutive active/androstane (CAR, NR1I3) are nuclear receptors characterized in 1998 by their capability to respond xenobiotics activate cytochrome P450 (CYP) genes. An anti-epileptic drug, phenobarbital (PB), activates CAR its target CYP2B genes, whereas PXR is activated drugs such as rifampicin statins for the CYP3A Inevitably, both have been investigated ligand-activated identifying characterizing therapeutics that directly bind and/or them. However, PB, which does not directly, presented an alternative research avenue indirect ligand-mediated activation mechanism: phosphorylation-mediated signal regulation. This review summarizes phosphorylation-based mechanisms utilized elicit cell signaling. First, presents how PB (and other receptors) through a conserved phosphorylation motif located between two zinc fingers within DNA-binding domain. PB-regulated at this enables form communication networks, integrating functions. Next, discusses xenobiotic-induced absence of domain motif. In case, occurs ligand-binding transduce signaling regulates hepatic energy metabolism. Finally, delves into implications disease development progression. was found induce own metabolism rat livers 1963 (1Remmer H. Merker H.J. Drug-induced changes liver endoplasmic reticulum: association with drug-metabolizing enzymes.Science. 1963; 142 (14075694): 1657-165810.1126/science.142.3600.1657Crossref PubMed Google Scholar). Subsequently, only but also various xenobiotic chemicals, polychlorobiphenyls, were shown drug (2Conney A.H. Pharmacological microsomal enzyme induction.Pharmacol. Rev. 1967; 19 (4383307): 317-366PubMed Scholar, 3Conney Burns J.J. Stimulatory effect foreign compounds on ascorbic acid biosynthesis enzymes.Nature. 1959; 184 (13811548): 363-36410.1038/184363a0Crossref Scopus (0) Over 40 years later, provided us experimental basis investigate cells exposures molecular level, greatly impacting pharmacology, toxicology, pathophysiology studies. Since discovered, over 70,000 manuscripts (PubMed search) published determined responses implicated developments therapies development. article focuses defining signal–regulated motifs determining mechanisms. For more comprehensive summary enormously expanded metabolism, readers referred overwhelming numbers already reviews. Here, we begin describing signals transduced PXR. NIEHS, National Institutes Health, constructed small mouse cDNA microarray late 1990s (4Ueda A. Hamadeh H.K. Webb Yamamoto Y. Sueyoshi T. Afshari C.A. Lehmann J.M. Negishi M. Diverse roles orphan regulating genes response phenobarbital.Mol. Pharmacol. 2002; 61 (11752199): 1-610.1124/mol.61.1.1Crossref (388) The first omics study CAR-regulated compared PB-treated from WT KO mice. be essential repress finding reciprocal regulation became understand extent diversity receptor–mediated transduction (Fig. 1). types omics, RNA-Seq, DNA ChIP-Seq, metabolomics, our understanding far beyond Drugs can metabolically toxicants or detoxified excretion, affecting efficacy causing side effects. Prodrugs activated. example, anti-cancer 5-fluorouracil 7-ethyl-10-hydroxycamptothecin (SN-38) prodrugs CYP2A6 carboxylesterases, respectively (5Ikeda K. Yoshisue Matsushima E. Nagayama S. Kobayashi Tyson Chiba Kawaguchi Bioactivation tegafur catalyzed P-450 2A6 human microsomes vitro.Clin Cancer Res. 2000; 6 (11106261): 4409-4415PubMed 6Satoh Hosokawa Atsumi R. Suzuki W. Hakusui Nagai Metabolic CPT-11, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin, novel antitumor agent, carboxylesterase.Biol. Pharm. Bull. 1994; 17 (7920428): 662-66410.1248/bpb.17.662Crossref 7Rivory L.P. Bowles M.R. Robert J. Pond S.M. Conversion irinotecan (CPT-11) active metabolite, (SN-38), carboxylesterase.Biochem. 1996; 52 (8831730): 1103-111110.1016/0006-2952(96)00457-1Crossref 8Humerickhouse Lohrbach Li L. Bosron W.F. Dolan M.E. Characterization CPT-11 hydrolysis carboxylesterase isoforms hCE-1 hCE-2.Cancer 60 (10728672): 1189-1192PubMed Naturally produced chemicals human-made environmental journey these same metabolic pathways toward respective excreted forms. Data analysis NIEHS gene expression array containing 8,736 138 either elevated repressed after treatment, regulated about half PB-altered encoded enzymes related included CYP2B10, aldehyde dehydrogenase I, esterase 1, flavin-containing monooxygenase, glutathione S-transferase, PAPS synthase 2, methyl transferase. produces donor substrate required mammalian sulfotransferases. δ-aminolaevulinic (δ-ALAS) rate-limiting step heme synthesis. Because prophetic group CYP known δ-ALAS, it reassuring observe induced δ-ALAS data. Unexpectedly, induction did appear dependent versus status. later demonstrated is, fact, (9Tojima Kakizaki Yamazaki Takizawa D. Horiguchi N. Sato Mori Ligand profiles PXR.Toxicol. Lett. 2012; 212 (22698814): 288-29710.1016/j.toxlet.2012.06.001Crossref (31) 10Columbano Ledda-Columbano G.M. Pibiri Cossu C. Menegazzi Moore D.D. Huang Tian Locker Gadd45β CAR-dependent, TNF-independent pathway murine hyperplasia.Hepatology. 2005; 42 (16231353): 1118-112610.1002/hep.20883Crossref induces NADPH-cytochrome reductase, enzymatic activity. appeared induction. addition enzymes, PXR) regulate many transporters modulate import excrete metabolites (11Klaassen C.D. Aleksunes L.M. Xenobiotic, bile acid, cholesterol transporters: function regulation.Pharmacol. 2010; 62 (20103563): 1-9610.1124/pr.109.002014Crossref (532) One RNA-Seq identified 2,125 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP)-regulated 5-pregnen-3β-ol-20-one-16α-carbonitrile (PCN)-regulated liver, among 147 (12Cui J.Y. Klaassen reveals common unique PXR- CAR-target signatures transcriptome.Biochim. Biophys. Acta. 2016; 1859 (27113289): 1198-121710.1016/j.bbagrm.2016.04.010Crossref (39) Many transporters. Another used CARKO, PXRKO, double-KO mice treated TCPOBOP PCN. 95% 554 affected treatment. Cyp3a11 Cyp2b10 PXR, Cyp1a1 Cyp1a2 A recent meta-analysis 22 data sets scope transcriptomes (13Ochsner S.A. Tsimelzon Dong Coarfa McKenna N.J. Research resource: reference transcriptome androstane signaling.Mol. Endocrinol. 30 (27409825): 937-94810.1210/me.2016-1095Crossref (3) It proteins, CYP2A4 CYP2A5, single amino mutation alter specificity (14Lindberg R.L. Alteration P450coh amino-acid residue.Nature. 1989; 339 (2733794): 632-63410.1038/339632a0Crossref numerous SNPs some resulted higher lower activities. Therefore, polymorphic mutations affect capacity metabolize drugs, increasing decreasing toxicity (15Pinto Clinically relevant genetic variations metabolizing enzymes.Curr. Drug Metab. 2011; 12 (21453273): 487-49710.2174/138920011795495321Crossref (73) 16Ingelman-Sundberg Sim S.C. Gomez Rodriguez-Antona Influence polymorphisms therapies: pharmacogenetic, pharmacoepigenetic clinical aspects.Pharmacol. Ther. 2007; 116 (18001838): 496-52610.1016/j.pharmthera.2007.09.004Crossref (850) Regulation expressions activities should critical humans bearing mutations. realized findings Pepck1 Cpt1a Fasn Hmgcs2 (17Rosenfeld Vargas Jr., Xie Evans R.M. Genetic profiling defines network controlled receptor.Mol. 2003; (12663745): 1268-128210.1210/me.2002-0421Crossref (190) Following findings, notion now accepted attenuates glucose augments lipid (18Kanno Otsuka Hiromasa Nakahama Inouye Diurnal difference mRNA expression.Nucl. Recept. 2004; 2 (15333129): 610.1186/1478-1336-2-6Crossref (21) 19Mackowiak B. Hodge Stern Wang receptors: chemical disposition.Drug Dispos. 2018; 46 (29759961): 1361-137110.1124/dmd.118.081042Crossref (23) 20Wada Gao metabolism.Trends 2009; 20 (19595610): 273-27910.1016/j.tem.2009.03.003Abstract Full Text PDF CAR, metabolomic studies detected increased decreased serum extracts treatment mice; those include fatty lactate, ketone bodies, tricarboxylic cycle products well (21Chen F. Coslo D.M. Chen Zhang Smith P.B. Patterson A.D. Omiecinski C.J. Metabolomic approaches reveal role metabolism.J. Proteome 2019; 18 (30336042): 239-25110.1021/acs.jproteome.8b00566PubMed Moreover, genome-wide ChIP-Seq competes HNF4α, PPARα, FXR binding sites, repressing (22Tian Marino Johnson Binding drug-activated CAR/Nr1i3 alters liver.iScience. 9 (30396153): 209-22810.1016/j.isci.2018.10.018Abstract growth, cycle, apoptosis GADD45B (10Columbano 23Yamamoto Flavell R.A. Lu represses TNFα-induced death interacting anti-apoptotic GADD45B.PLoS One. 5 (20404936): e1012110.1371/journal.pone.0010121Crossref Cdc20 Cdk1 c-Myc Gadd45b ectopically expressing GFP-tagged ∼1,000 differentially including protooncogene Myc Ikbke, (24Niu Bataille A.R. Albert I. Pugh B.F. vivo interactions targets.Nucleic Acids (30102401): 8385-840310.1093/nar/gky692Crossref (11) Yes-associated protein (YAP) hepatocyte growth proliferation (25Abe Amaike Shizu Takahashi Kano Hosaka Sasaki Kodama Matsuzawa Yoshinari Role YAP CAR-mediated hepatocytes.Toxicol. Sci. 165 (29893953): 408-41910.1093/toxsci/kfy149Crossref (10) 26Abe Shimizu Functional interaction xenobiotic-dependent hypertrophy Exp. 371 (31533970): 590-60110.1124/jpet.119.258632Crossref (2) 27Jiang Feng Ma X. Fan Fu Sun Yao Liu Xu Gonzalez F.J. Yang et al.Pregnane size fate mice.Hepatology. 69 (30048004): 343-35810.1002/hep.30131Crossref (25) More additional information growth. urine decreases vitamin E activation. suggested may signals. humans, altered steroids samples; sulfate conjugates dehydroepiandrosterone androsterone increased, hydroxylated C-19 androgens (28Kim Moon Choi M.H. H.H. Lee Lim K.S. Yoon S.H. Yu Jang I.J. Cho Global metabolomics targeted steroid rifampin, strong activator, endogenous urinary markers.J. 2013; (23320515): 1359-136810.1021/pr301021pCrossref Scholar), suggesting involvement Various noncoding RNAs reported actions (29Nakano Nakajima Current knowledge microRNA-mediated humans.Expert Opin. Toxicol. 14 (29718737): 493-50410.1080/17425255.2018.1472237Crossref direct indirectly cellular combination both. Hereafter, regulator. contain Thr Ser residues potential molecules (30Treviño L.S. Weigel N.L. Phosphorylation: fundamental regulator action.Trends 24 (23838532): 515-52410.1016/j.tem.2013.05.008Abstract early emphasis observed hormone receptors, while searching regulations (so-called ligand-independent mechanism) hormone-binding mechanism. consist similar-sized DNA- domains (DBDs LBDs) 350–400 N-terminal (NTDs) lengths 2). Steroid possess long NTDs, androgen having longest 600 residues, includes 1 (AF1). investigations NTD impeding efforts corroborate conceptualize receptors. As (33Matalon O. Dubreuil Levy E.D. Young functionally silent.Science. 354 (27738157): 176-17710.1126/science.aai8833Crossref (1) 34Studer Rodriguez-Mias Haas K.M. Hsu J.I. Viéitez Solé Swaney D.L. Stanford L.B. Liachko Böttcher Dunham M.J. de Nadal Posas Beltrao P. Villén Evolution across fungal species.Science. (27738172): 229-23210.1126/science.aaf2144Crossref (41) last 1.8 million functional. Meanwhile, DBD LBD less emphasized targets investigation. functions had clearly defined ligand bindings, conducted under ligand-dependent concept. throughout species separated 70 evolution. These evolutionarily likely inherit short 39 respectively, helping repeat history lead LBD. conserve LBD, Our focused Thr-38 Ser-350 respectively. high conservation species, what could extended finger initially examined focusing Thr-38. Zinc structural widely present proteins kingdoms living organisms. divided different (fold groups) often represented classic C2H2, ribbon, treble clef (TC)-folds (35Krishna S.S. Majumdar Grishin N.V. Structural classification fingers: survey summary.Nucleic 31 (12527760): 532-55010.1093/nar/gkg161Crossref (548) main TC-fold binding. comprises classical NR receptor–like family (36Kaur G. Subramanian Classification finger: noteworthy lessons structure evolution.Sci. Rep. (27562564): 3207010.1038/srep32070Crossref Metazoan kingdom. case domains, peptides 26 32 β-strand, loop, α-helix, four coordinate one atom loop words, pairs cysteine knuckle (CXXC) N terminus 2B). Two connected via linker double loops DBD. five α-helix proximal box (P-box), interacts inserting major groove strands. C-terminal typical TC-fold; three-amino residue segment inserted region constitute D-box (distal dimerization residues). feature involved intramolecular interactions, Amino sequences well-conserved polar (threonine serine) positively charged lysine incorporated during evolution, creating kinase C, A, p38 MAPK motifs. Among them, Thr/Ser-10, Thr/Ser-18, Tyr-14, Tyr-38 relatively well-conserved, 44, 37, 43, 41 total S1). Retinoic α (RARα) conserves Thr/Ser-10 Ser-96. RARα constitutively receptor. AKT-phosphorylated Ser-96 transformed prevents heterodimerizing retinoid (RXRα) transactivation activity (37Srinivas Xia Uray I.P. Kim Brown P.H. Kurie Akt phosphorylates suppresses retinoic alpha.Biochem. 2006; 395 (16417524): 653-66210.1042/BJ20051794Crossref (35) Human Ser-135. phosphorylation-blocking (S135A) prohibits RXRα, abrogating (38Gineste Sirvent Paumelle Helleboid Aquilina Darteil Hum D.W. Fruchart J.C. Staels Phosphorylation farnesoid C promotes transcriptional activity.Mol. 2008; (18755856): 2433-244710.1210/me.2008-0092Crossref (56) retains corresponds Thr-57. T57A attenuated PXR's ability CYP3A4 promoter cell-based assays (39Lichti-Kaiser Brobst Staudinger J.L. systematic predicted sites protein.J. 331 (19617467): 65-7610.1124/jpet.109.157180Crossref 40Pondugula S.R. Brimer-Cline Wu Schuetz E.G. Tyagi R.K. phosphomimetic threonine-57 abolishes localization pattern x receptor.Drug 37 (19171678): 719-73010.1124/dmd.108.024695Crossref has confirmed animal tissues. motif, corresponding counterparts Only do retain motif: members (NR3C subfamily). Thr/Ser-29 positioned middle finger, connecting finger. most extensively (41Mutoh Osabe Inoue Pedersen Perera Rebolloso Dephosphorylation threonine 38 translocation (NR1I3).J. Biol. Chem. 284 (19858220): 34785-3479210.1074/jbc.M109.048108Abstract (105) 42Mutoh Sobhany Phenobarbital (CAR) inhibition epidermal factor signaling.Sci. Signal. (23652203): ra3110.1126/scisignal.2003705Crossref (126) 43Negishi meets receptors.Drug 2017; 45 (28356313): 532-53910.1124/dmd.116.074872Crossref (19) 44Osabe Active ERK1/2 phosphorylated (CAR; NR1I3), dephosphorylation sequestering cytoplasm.J. 286 (21873423): 35763-3576910.1074/jbc.M111.284596Abstract (42) 45Yang Garzel Heyward Moeller Shapiro Metformin drug-induced CYP2B6 modulating 2014; 85 (24252946): 249-26010.1124/mol.113.089763Crossref 46Shizu Min L.C. Mutoh Interaction activation.J. 293 (29133527): 333-34410.1074/jbc.M117.806604Abstract

Language: Английский

---

RISING STARS: Sex differences in toxicant-associated fatty liver disease

Journal of Endocrinology, Journal Year: 2023, Volume and Issue: 258(1)

Published: April 19, 2023

Based on biological sex, the consequential health outcomes from exposures to environmental chemicals or toxicants can differ in disease pathophysiology, progression, and severity. Due basal differences cellular molecular processes resulting sexual dimorphism of organs including liver additional factors influencing ‘gene–environment’ interactions, males females exhibit different responses toxicant exposures. Associations between environmental/occupational chemical fatty (FLD) have been well-acknowledged human epidemiologic studies their causal relationships demonstrated experimental models. However, related sex toxicology are still limited draw any inferences sex-dependent toxicity. The purpose this review is highlight present state knowledge existence toxicant-associated FLD (TAFLD), discuss potential underlying mechanisms driving these differences, implications said susceptibility, emerging concepts. Chemicals interest include various categories pollutants that investigated TAFLD, namely persistent organic pollutants, volatile compounds, metals. Insight into research areas requiring further development also discussed, with objective narrowing gap diseases. Major conclusions exercise influences TAFLD risks, part due (i) disruption growth hormone estrogen receptor signaling, (ii) energy mobilization storage, (iii) metabolism subsequent body burden. Finally, toxicological assessments warranted for sex-specific intervention strategies.

Language: Английский

---

Aryl hydrocarbon receptor: current perspectives on key signaling partners and immunoregulatory role in inflammatory diseases

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Aug. 15, 2024

The aryl hydrocarbon receptor (AhR) is a versatile environmental sensor and transcription factor found throughout the body, responding to wide range of small molecules originating from environment, our diets, host microbiomes, internal metabolic processes. Increasing evidence highlights AhR’s role as critical regulator numerous biological functions, such cellular differentiation, immune response, metabolism, even tumor formation. Typically located in cytoplasm, AhR moves nucleus upon activation by an agonist where it partners with either nuclear translocator (ARNT) or hypoxia-inducible 1β (HIF-1β). This complex then interacts xenobiotic response elements (XREs) control expression key genes. notably present various crucial cells, recent research underscores its significant impact on both innate adaptive immunity. review delves into latest insights structure, activating ligands, multifaceted roles. We explore sophisticated molecular pathways through which influences lymphoid emphasizing emerging importance managing inflammatory diseases. Furthermore, we discuss exciting potential developing targeted therapies that modulate activity, opening new avenues for medical intervention immune-related conditions.

Language: Английский

---

Exposure to persistent organic pollutants: impact on women’s health

Reviews on Environmental Health, Journal Year: 2018, Volume and Issue: 33(4), P. 331 - 348

Published: Aug. 15, 2018

Abstract This literature review focuses on the causal relationship between persistent organic pollutants (POPs) exposure and women’s health disorders, particularly cancer, cardio-metabolic events reproductive health. Progressive industrialization has resulted in production of a multitude chemicals that are released into environment daily basis. Environmental or not only hazardous to our ecosystem but also lead various problems affect human population worldwide irrespective gender, race age. However, most environmental studies have been conducted, until recently, were exclusively biased with regard sex beginning reported mostly male, occupational workers animal being carried out male rodent models. Health-related issues pertaining women all age groups studied thoroughly rather disregarded aspects basic science research it is therefore pertinent we address these limitations The addresses looking at associations outcomes exposures POPs, particularly, polychlorinated biphenyls (PCBs), dioxins pesticides, cohort while accounting for gender differences. Considering current levels POPs can impact future generations, informative guidelines related dietary patterns history needed Additionally, cohorts highly exposed worldwide, such as working manufacturing plants female pesticide applicators required gather more information susceptibility disease pathology.

Language: Английский

---