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. 2021 Jul 8;40(8):2165–2182. doi: 10.1002/etc.5118

Table 2.

Adverse outcome pathways (AOPs) and functional gene annotations relevant to ToxCast assays associated with chemical mixtures and individual chemicals with exposure activity ratios >10–3 at 10% or more of monitored sitesa

Gene: assay: chemical/mixture AOPs: overview Functional annotationsb No. sites

AR:

ACEA_AR_antagonist_80hr:

dl‐Menthol

 Five AOPs under developmentc; developmental and reproductive toxicity; mammals [1: Oocyte meiosis, pathways in cancer, prostate cancer]; [2: prostate cancer, susceptibility to; androgen insensitivity; hypospadias 1, X‐linked; androgen insensitivity, partial, with or without breast cancer; spinal and bulbar muscular atrophy of Kennedy]; [3: Danio rerio: transcription, DNA‐templated; regulation of transcription, DNA‐templated; steroid hormone–mediated signaling pathway]. 9

AHR:

ATG_Ahr_CIS_up:

Benz[a]anthracene, indeno[1,2,3‐cd]

pyrene

 Three OECD‐endorsed AOPsd; 3 AOPs open for citatione; 2 AOPs under developmentc; early–life stage mortality; hepatic steatosis; liver tumors; uroporphyria; developmental toxicity [1: Response to xenobiotic stimulus]; [3: Oryzias latipes: transcription, DNA‐templated; regulation of transcription, DNA‐templated] 17

AHR:

TOX21_AhR_LUC_Agonist:

Benzo[b]fluoranthene, benzo[k]

fluoranthene

 Three OECD‐endorsed AOPsd; 3 AOPs open for citatione; 2 AOPs under developmentc; early–life stage mortality; hepatic steatosis; liver tumors; uroporphyria; developmental toxicity [1: Response to xenobiotic stimulus]; [3: Oryzias latipes: transcription, DNA‐templated; regulation of transcription, DNA‐templated] 17

CYP1A2:

CLD_CYP1A2_24hr: Atrazine

 Two OECD‐endorsed AOPsf; one AOP open for citationg; early–life stage mortality; liver tumors; uroporphyria [1: Steroid hormone biosynthesis, caffeine metabolism, tryptophan metabolism, linoleic acid metabolism, retinol metabolism, metabolism of xenobiotics by cytochrome P450, drug metabolism by cytochrome P450, metabolic pathways, chemical carcinogenesis] 11

CYP19A1:

NVS_ADME_hCYP19A1: DEHP

 One OECD‐endorsed AOPh; one AOP open for citationi; 2 AOPs under developmentc; impaired fertility, reproductive dysfunction, male‐biased sexual differentiation [1: Steroid hormone biosynthesis, metabolic pathways, ovarian steroidogenesis]; [2: aromatase excess syndrome, aromatase deficiency] 10

CYP2B6:

CLD_CYP2B6_24hr: Atrazine;

CLD_CYP2B6_6hr: Atrazine, DEET

 Not applicable [1: Arachidonic acid metabolism, retinol metabolism, metabolism of xenobiotics by cytochrome P450, drug metabolism by cytochrome P450, metabolic pathways]; [2: efavirenz central nervous system toxicity, susceptibility to and poor metabolism of] 10; 18

ESR1:

ACEA_ER_80hr:

TBEP, p‐tert‐octylphenol, triethyl citrate

 Six AOPs under developmentc, j; developmental and reproductive toxicity; increased cancer risk [1: Estrogen signaling pathway, prolactin signaling pathway, thyroid hormone signaling pathway, endocrine and other factor–regulated calcium reabsorption, proteoglycans in cancer]; [2: breast cancer; migraine, susceptibility to; myocardial infarction, susceptibility to; estrogen resistance; atherosclerosis, susceptibility to; HDL response to hormone replacement, augmented]; [3: Danio rerio: transcription, DNA‐templated; regulation of transcription, DNA‐templated; response to xenobiotic stimulus; response to estradiol; steroid hormone–mediated signaling pathway; response to estrogen; posterior lateral line neuromast primordium migration; cellular response to estrogen stimulus] 7

ESR1, ESR2:

CEETOX_H295R_ESTRONE_up:

Atrazine

 Not applicable [1: Estrogen signaling pathway, prolactin signaling pathway, thyroid hormone signaling pathway, endocrine and other factor–regulated calcium reabsorption, proteoglycans in cancer]; [2: breast cancer; migraine, susceptibility to; myocardial infarction, susceptibility to; estrogen resistance; atherosclerosis, susceptibility to; HDL response to hormone replacement, augmented]; [3: Danio rerio: transcription, DNA‐templated; regulation of transcription, DNA‐templated; response to xenobiotic stimulus; response to estradiol; steroid hormone–mediated signaling pathway; response to estrogen; posterior lateral line neuromast primordium migration; cellular response to estrogen stimulus] 16

NR1I2:

ATG_PXR_TRANS_up: Atrazine, TCPP,

TDCPP; ATG_PXRE_CIS_up:

Atrazine, DEHP, TBEP, TCPP

TDCPP

 One AOPj; hepatic steatosis [3: Danio rerio: transcription, DNA‐templated; regulation of transcription, DNA‐templated; transcription from RNA polymerase II promoter; response to toxic substance; steroid hormone–mediated signaling pathway] 7; 8

PDE4A:

NVS_ENZ_hPDE4A1: Atrazine

 Not applicable [1: Purine metabolism, cAMP signaling pathway, morphine addiction]; [3: Danio rerio: signal transduction] 23

SOX1:

ATG_Sox_CIS_up: Caffeine

 Not applicable [3: Oryzias latipes: regulation of transcription, DNA‐templated; nervous system development; positive regulation of sequence‐specific DNA binding transcription factor activity] 9

TSPO:

NVS_MP_hPBR:

DEHP, TBEP, tributyl phosphate,

TCPP, TDCPP

 Not applicable [1: Neuroactive ligand–receptor interaction, HTLV‐I infection]; [3: Danio rerio: primitive erythrocyte differentiation] 10
a

ToxCast assay name; AOP overview provides a listing of relevant AOPs from the AOP‐Wiki and an overview of associated apical outcomes; official gene symbol for gene target associated with ToxCast assays; functional gene annotations from DAVID 6.8.

b

Annotation sources [1: Kyoto Encyclopedia of Genes and Genomes pathways (Homo sapiens)]; [2: Online Mendelian Inheritance in Man Disease (Homo sapiens)]; [3: GO Biological Process for a representative fish species]. If not listed for a given annotation source, no annotations were available for that source.

DEHP = di(2‐ethylhexyl)phthalate; DEET = N,N‐diethyltoluamide; TBEP = tris(2‐butoxyethyl) phosphate; TCPP = tris(2‐chloroisopropyl)phosphate; TDCPP = tris(1,3‐dichloro‐2‐propyl)phosphate; OECD = Organisation for Economic Co‐operation and Development; HTLV‐I human T‐cell lymphotropic virus type 1.