The role of receptor‐mediated activities of 4‐ and 5‐ring unsubstituted and methylated polycyclic aromatic hydrocarbons (PAHs) in developmental toxicity

The present study evaluated the aryl hydrocarbon receptor (AhR), estrogen receptor‐α (ER‐α), and retinoic acid receptor (RAR) mediated activities of nine 4‐ and 5‐ring unsubstituted and monomethylated polycyclic aromatic hydrocarbons (PAHs) using a series of Chemical‐Activated LUciferase gene eXpression (CALUX) assays. The potential role of these aforementioned receptors in relation to the developmental toxicity of these PAHs was further assessed in the zebrafish embryotoxicity test (ZET). The results show that all nine tested PAHs were AhR agonists, benz[a]anthracene (BaA) and 8‐methyl‐benz[a]anthracene (8‐MeBaA) were ER‐α agonists, and none of the tested PAHs induced ER‐α antagonistic or RAR (ant)agonistic activities. In the AhR CALUX assay, all the methylated PAHs showed higher potency (lower EC50) in activating the AhR than their respective unsubstituted PAHs, implying that the addition of a methyl substituent on the aromatic ring of PAHs could enhance their AhR‐mediated activities. Co‐exposure of zebrafish embryos with each individual PAH and an AhR antagonist (CH223191) counteracted the observed developmental retardations and embryo lethality to a certain extent, except for 8‐methyl‐benzo[a]pyrene (8‐MeBaP). Co‐exposure of zebrafish embryos with either of the two estrogenic PAHs (i.e., BaA and 8‐MeBaA) and an ER‐α antagonist (fulvestrant) neutralized embryo lethality induced by 50 μM BaA and the developmental retardations induced by 15 μM 8‐MeBaA. Altogether, our findings suggest that the observed developmental retardations in zebrafish embryos by the PAH tested may partially be AhR‐ and/or ER‐α‐mediated, whereas the RAR seems not to be relevant for the PAH‐induced developmental toxicity in the ZET.

• Publication year

  2022

• Venue

  Journal of Applied Toxicology

• Publication date

  2022-12-30

• Fields of study

  Medicine, Chemistry, Environmental Science

• Identifiers
  DOI 10.1002/jat.4428PMID 36585251
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Developmental toxicity testing of unsubstituted and methylated 4- and 5-ring polycyclic aromatic hydrocarbons using the zebrafish embryotoxicity test.

  2022cited by this paper
• Developmental toxicity testing of the fume condensate extracts of bitumen and oxidized asphalt in a series of in vitro alternative assays.

  2021cited by this paper
• Assessment of the in vitro developmental toxicity of diethylstilbestrol and estradiol in the zebrafish embryotoxicity test.

  2021cited by this paper
• Comparative Study

  2020cited by this paper
• Assessing the receptor-mediated activity of PAHs using AhR-, ERα- and PPARγ- CALUX bioassays.

  2020cited by this paper
• Retention Behaviour of Alkylated and Non-Alkylated Polycyclic Aromatic Hydrocarbons on Different Types of Stationary Phases in Gas Chromatography

  2019cited by this paper
• The role of metabolism in the developmental toxicity of polycyclic aromatic hydrocarbon‐containing extracts of petroleum substances

  2019cited by this paper
• In vitro prenatal developmental toxicity induced by some petroleum substances is mediated by their 3- to 7-ring PAH constituent with a potential role for the aryl hydrocarbon receptor (AhR).

  2019cited by this paper
• Sources and environmental fate of pyrogenic polycyclic aromatic hydrocarbons (PAHs) in the Arctic

  2019cited by this paper
• The Role of Endocrine and Dioxin-Like Activity of Extracts of Petroleum Substances in Developmental Toxicity as Detected in a Panel of CALUX Reporter Gene Assays

  2018influential reference
• AhR signaling pathways and regulatory functions

  2018cited by this paper
• Prenatal developmental toxicity testing of petroleum substances using the zebrafish embryotoxicity test.

  2018cited by this paper
• Methylated PACs are more potent than their parent compounds: A study of aryl hydrocarbon receptor–mediated activity, degradability, and mixture interactions in the H4IIE‐luc assay

  2018cited by this paper
• Polycyclic Aromatic Hydrocarbons as Environmental Pollutants: A review

  2017cited by this paper
• Developmental benzo[a]pyrene (B[a]P) exposure impacts larval behavior and impairs adult learning in zebrafish.

  2017cited by this paper
• Assessment of the aryl hydrocarbon receptor-mediated activities of polycyclic aromatic hydrocarbons in a human cell-based reporter gene assay.

  2017cited by this paper
• Theoretical and mathematical foundation of the Virtual Cell Based Assay - A review.

  2017cited by this paper
• Prenatal developmental toxicity testing of petroleum substances: Application of the mouse embryonic stem cell test (EST) to compare in vitro potencies with potencies observed in vivo.

  2017influential reference
• Retinoic Acid Embryopathy

  2017cited by this paper
• Retinoic acid in developmental toxicology: Teratogen, morphogen and biomarker.

  2017cited by this paper
• Review of endocrine disorders associated with environmental toxicants and possible involved mechanisms.

  2016cited by this paper
• AZD9496: An Oral Estrogen Receptor Inhibitor That Blocks the Growth of ER-Positive and ESR1-Mutant Breast Tumors in Preclinical Models.

  2016influential reference
• Investigation of the effects of estrogen on skeletal gene expression during zebrafish larval head development

  2016cited by this paper
• Dose metric considerations in in vitro assays to improve quantitative in vitro-in vivo dose extrapolations.

  2015cited by this paper
• Quantitative structure-activity relationships for chronic toxicity of alkyl-chrysenes and alkyl-benz[a]anthracenes to Japanese medaka embryos (Oryzias latipes).

  2015cited by this paper
• Aryl hydrocarbon receptor activation and developmental toxicity in zebrafish in response to soil extracts containing unsubstituted and oxygenated PAHs.

  2015cited by this paper
• Estrogen receptor signaling during vertebrate development.

  2015cited by this paper
• From cutting edge to guideline: A first step in harmonization of the zebrafish embryotoxicity test (ZET) by describing the most optimal test conditions and morphology scoring system.

  2015cited by this paper
• Methylated phenanthrenes are more potent than phenanthrene in a bioassay of human aryl hydrocarbon receptor (AhR) signaling

  2014cited by this paper
• Mono-substituted isopropylated triaryl phosphate, a major component of Firemaster 550, is an AHR agonist that exhibits AHR-independent cardiotoxicity in zebrafish.

  2014cited by this paper
• Development of a methodology for accurate quantitation of alkylated polycyclic aromatic hydrocarbons in petroleum and oil contaminated environmental samples

  2014cited by this paper
• Comparative embryotoxicity of phenanthrene and alkyl-phenanthrene to marine medaka (Oryzias melastigma).

  2014cited by this paper
• Development of a panel of high-throughput reporter-gene assays to detect genotoxicity and oxidative stress.

  2014cited by this paper
• Identification and quantification of methylated PAHs in sediment by two-dimensional gas chromatography/mass spectrometry

  2013cited by this paper
• Structurally distinct polycyclic aromatic hydrocarbons induce differential transcriptional responses in developing zebrafish.

  2013cited by this paper
• Aryl phosphate esters within a major PentaBDE replacement product induce cardiotoxicity in developing zebrafish embryos: potential role of the aryl hydrocarbon receptor.

  2013influential reference
• Predicting adult fish acute lethality with the zebrafish embryo: relevance of test duration, endpoints, compound properties, and exposure concentration analysis.

  2012cited by this paper
• Developmental toxicity and endocrine disrupting potency of 4-azapyrene, benzo[b]fluorene and retene in the zebrafish Danio rerio.

  2012cited by this paper
• Benzo[a]pyrene exposure influences the cardiac development and the expression of cardiovascular relative genes in zebrafish (Danio rerio) embryos.

  2012cited by this paper
• Establishing Criteria of Relative Abundance of Alkyl Polycyclic Aromatic Hydrocarbons (PAHs) for Differentiation of Pyrogenic and Petrogenic PAHs: An Application to Indian Sediment

  2012cited by this paper
• AHR2 Mutant Reveals Functional Diversity of Aryl Hydrocarbon Receptors in Zebrafish

  2012cited by this paper
• Quantifying processes determining the free concentration of phenanthrene in Basal cytotoxicity assays.

  2012influential reference
• Measuring the toxicity of alkyl‐phenanthrenes to early life stages of medaka (Oryzias latipes) using partition‐controlled delivery

  2011cited by this paper
• AHR2 knockdown prevents PAH-mediated cardiac toxicity and XRE- and ARE-associated gene induction in zebrafish (Danio rerio).

  2011cited by this paper
• Toxic effects of methylated benzo[a]pyrenes in rat liver stem-like cells.

  2011cited by this paper
• The application of reporter gene assays for the detection of endocrine disruptors in sport supplements.

  2011cited by this paper
• Superinduction of estrogen receptor mediated gene expression in luciferase based reporter gene assays is mediated by a post-transcriptional mechanism.

  2010cited by this paper
• CH223191 is a ligand-selective antagonist of the Ah (Dioxin) receptor.

  2010influential reference
• Measuring, modeling, and increasing the free Concentration of test Chemicals in cell assays

  2010cited by this paper
• Is the fish embryo toxicity test (FET) with the zebrafish (Danio rerio) a potential alternative for the fish acute toxicity test?

  2009cited by this paper
• Specific in vitro toxicity of crude and refined petroleum products. 1. Aryl hydrocarbon receptor—mediated responses

  2009cited by this paper
• Sources of sedimentary PAHs in tropical Asian waters: differentiation between pyrogenic and petrogenic sources by alkyl homolog abundance.

  2009cited by this paper
• Function of retinoic acid receptors during embryonic development

  2009cited by this paper
• Toxic effects of methylated benz[a]anthracenes in liver cells.

  2008cited by this paper
• Polycyclic Aromatic Hydrocarbons in Food - Scientific Opinion of the Panel on Contaminants in the Food Chain

  2008cited by this paper
• Prenatal Exposure to Airborne Polycyclic Aromatic Hydrocarbons and Risk of Intrauterine Growth Restriction

  2008cited by this paper
• Retinoic acid.

  2008cited by this paper
• Specific in vitro toxicity of crude and refined petroleum products

  2007cited by this paper
• Effect of Prenatal Exposure to Airborne Polycyclic Aromatic Hydrocarbons on Neurodevelopment in the First 3 Years of Life among Inner-City Children

  2006cited by this paper
• International Studies of Prenatal Exposure to Polycyclic Aromatic Hydrocarbons and Fetal Growth

  2006cited by this paper
• The role of the aryl hydrocarbon receptor pathway in mediating synergistic developmental toxicity of polycyclic aromatic hydrocarbons to zebrafish.

  2006cited by this paper
• Developmental toxicity of 4-ring polycyclic aromatic hydrocarbons in zebrafish is differentially dependent on AH receptor isoforms and hepatic cytochrome P4501A metabolism.

  2006influential reference
• PAH-DNA adducts in cord blood and fetal and child development in a Chinese cohort.

  2006cited by this paper
• Formation of estrogenic metabolites of benzo[a]pyrene and chrysene by cytochrome P450 activity and their combined and supra-maximal estrogenic activity.

  2005cited by this paper
• Chemically activated luciferase gene expression (CALUX) cell bioassay analysis for the estimation of dioxin-like activity: critical parameters of the CALUX procedure that impact assay results.

  2005cited by this paper
• Ah receptor signals cross-talk with multiple developmental pathways.

  2005cited by this paper
• Differential action of polycyclic aromatic hydrocarbons on endogenous estrogen-responsive genes and on a transfected estrogen-responsive reporter in MCF-7 cells.

  2004cited by this paper
• Effects of transplacental exposure to environmental pollutants on birth outcomes in a multiethnic population.

  2003cited by this paper
• Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals.

  2003cited by this paper
• Identification of Endocrine Disruptive Effects in theAquatic Environment - a Partial Life Cycle Study in Zebrafish

  2003cited by this paper
• Role of the aryl hydrocarbon receptor in cell cycle regulation.

  2002cited by this paper
• Role of the aryl hydrocarbon receptor in cell cycle regulation.

  2002cited by this paper
• Alteration of pregnancy related hormones and fetal survival in F-344 rats exposed by inhalation to benzo(a)pyrene.

  2002cited by this paper
• Hydroxylated benzo[a]pyrene metabolites are responsible for in vitro estrogen receptor-mediated gene expression induced by benzo[a]pyrene, but do not elicit uterotrophic effects in vivo.

  2001cited by this paper
• Aryl hydrocarbon receptor-mediated activity of mutagenic polycyclic aromatic hydrocarbons determined using in vitro reporter gene assay.

  2001cited by this paper
• Interaction of PAH-related compounds with the alpha and beta isoforms of the estrogen receptor.

  2001cited by this paper
• Interaction of PAH-related compounds with the α and β isoforms of the estrogen receptor

  2001cited by this paper
• Estrogen and xenoestrogens upregulate the brain aromatase isoform (P450aromB) and perturb markers of early development in zebrafish (Danio rerio).

  2001cited by this paper
• The application of reporter gene assays for the determination of the toxic potency of diffuse air pollution.

  2000cited by this paper
• Activity of benzo[a]pyrene and its hydroxylated metabolites in an estrogen receptor-alpha reporter gene assay.

  2000cited by this paper
• Teratology Society Public Affairs Committee position paper: developmental toxicity of endocrine disruptors to humans.

  1999cited by this paper
• Toxicity of retene to early life stages of two freshwater fish species

  1999cited by this paper
• Environmental antiandrogens: developmental effects, molecular mechanisms, and clinical implications

  1997cited by this paper
• The anti-estrogenic activity of selected polynuclear aromatic hydrocarbons in yeast expressing human estrogen receptor.

  1996cited by this paper
• Species-specific antagonism of Ah receptor action by 2,2',5,5'-tetrachloro- and 2,2',3,3'4,4'-hexachlorobiphenyl.

  1995cited by this paper
• Teratogenic effects of retinoic acid and related substances on the early development of the zebrafish (Brachydanio rerio) as assessed by a novel scoring system.

  1995cited by this paper
• The molecular and cell biology of anion transport by bacteria

  1992cited by this paper
• A comparative study of the reproductive effects of methadone and benzo[a]pyrene in the pregnant and pseudopregnant rat.

  1986cited by this paper
• Retinoic acid embryopathy.

  1985cited by this paper

• Risk assessment of four polycyclic aromatic hydrocarbons in South Korean sesame oil products

  2025cites this paper
• Position-specific methyl substitution on benzo[a]pyrene drives AHR-dependent fin duplication in zebrafish

  2025cites this paper
• Effect of luminescent materials on the biochemistry, ultrastructure, and rhizobial microbiota of Spirodela polyrhiza.

  2024cites this paper
• Structure-based modeling to assess binding and endocrine disrupting potential of polycyclic aromatic hydrocarbons in Danio rerio.

  2024cites this paper
• Synthesis of novel rapanone derivatives via organocatalytic reductive C-alkylation: biological evaluation of antioxidant properties, in vivo zebrafish embryo toxicity, and docking studies.

  2024cites this paper
• Exploring the endocrine disrupting potential of a complex mixture of PAHs in the estrogen pathway in Oreochromis niloticus hepatocytes.

  2024cites this paper
• Developmental toxicity of alkylated PAHs and substituted phenanthrenes: Structural nuances drive diverse toxicity and AHR activation

  2024cites this paper
• AHR-mediated m6A RNA methylation contributes to PM2.5-induced cardiac malformations in zebrafish larvae.

  2023cites this paper
• Systematic computational toxicity analysis of the ozonolytic degraded compounds of azo dyes: Quantitative structure-activity relationship (QSAR) and adverse outcome pathway (AOP) based approach.

  2023cites this paper
• Evaluating the in vitro developmental toxicity potency of a series of petroleum substance extracts using new approach methodologies (NAMs)

  2023cites this paper