Table 4.

Developmental Toxicity Endpoints and Cyp1a Expression Patterns Mediated by AHR2 From Morpholino Knockdown Studies

Xenobiotic Ligand	Endpoints Mediated by Ligand x AHR2	Results of AHR2 Knockdown	References
Polycyclic Aromatic Hydrocarbons (PAHs)
Pyrene	Pericardial edema, cell death in the neural tube, anemia- Cyp1a protein expression	Prevention of morphological effects Reduced vasculature expression	Incardona et al. (2005)
Chrysene	Cyp1a protein expression	Prevention of epidermal expression No change to vasculature expression	Incardona et al. (2005)
Dibenzothiophene	Cyp1a protein expression	Reduction of weak vascular expression No change to cardiotoxicity	Incardona et al. (2005)
Phenanthrene	Cyp1a protein expression	Reduction of weak vascular expression No change to cardiotoxicity	Incardona et al. (2005)
Benz[a]anthracene (BAA)	Pericardial edema Intracranial hemorrhage Cyp1a protein expression	Reduction in prevalence of pericardial edema Prevention Reduction in ventricular myocardium and epidermis No reduction in endocardial and other vascular endothelial Cyp1a protein induction	Incardona et al. (2006, 2011)
Benzo[a]pyrene (BaP)	Pericardial edema Cyp1a protein expression Larval hyperactive swimming response	Partial protection Loss of myocardial expression No reduction in endocardial expression Decreased larval swimming response	Cunha et al. (2020); Incardona et al. (2011); Knecht et al. (2017b)
Benzo[k]fluoranthene   (BkF)	Cyp1a protein expression	Markedly reduced epidermal Cyp1a expression No reduction in endocardial expression or pericardial edema	Incardona et al. (2011)
Retene	Pericardial edema Cyp1a protein expression	Prevalence and severity of pericardial edema lower Reduced epidermal expression No change to vascular expression	Scott et al. (2011)
Benz(a)anthracene-7,12-dione (7,12-B[a]AQ)	Morphology malformations: axis, trunk, brain, yolk and pericardial edemas, circulation, eye and jaw malformations Cyp1a protein expression	Prevention Prevention of vasculature expression	Goodale et al. (2015); Knecht et al. (2013)
1,9-Benz-10-anthrone (BEZO)	Morphology malformations: axis, trunk, brain, yolk and pericardial edemas, circulation, eye and jaw malformations	Prevention	Goodale et al. (2015)
1,6-Dinitropyrene,	Cyp1a protein expression	Reduction in skin and vasculature	Chlebowski et al. (2017)
benzo[j]fluoranthene, dibenzo[a.h]pyrene, dibenzo[a,i]pyrene, and benzo[b]fluoranthene	Cyp1a protein expression	Reduction in vasculature and prevention of skin expression	Shankar et al. (2019)
6H-benzo[cd]pyren-6-one	Cardiotoxicity	Prevention	Cunha et al. (2020)
Other chemicals: mixtures, pharmaceuticals, indoles, and halogenated aromatic hydrocarbons
PAH-containing soil extracts from a gasworks, a former wood preservation site, and a coke oven	Edema and viability	Decrease in edema occurrence, and increase in viability	Wincent et al. (2015)
Total particulate matter (cigarette smoke)	Several morphological endpoints, viability, hatching success	Reduction in morphological endpoints, increased viability and hatching success	Massarsky et al. (2016)
Environmentally relevant PAH mixtures (“Supermix 3” and “Supermix 10”)	Cyp1a protein expression	Supermix 3: decrease invasculature expression and increase in liver expression —Supermix 10: persistence of both vasculature and liver expression	Geier et al. (2018b)
BaP and 6H-benzo[cd]pyren-6-one	Cardiotoxicity (pericardial edema and string heart formation)	Prevention	Cunha et al. (2020)
Cardiosulfa (sulfanomide drug)	Cardiotoxicity	Reduction	Ko and Shin (2012); Ko et al. (2009)
Leflunomide	Cyp1a protein expression	Reduction	Goodale et al. (2012); O’Donnell et al. (2010)
3,3’,4,4’,5-Pentachlorobiphenyl (PCB-126)	Cardiotoxicity and mortality	Reduction	Garner et al. (2013); Jonsson et al. (2007)
Monosubstituted isopropyl triaryl phosphate (mITP) (a major component of Firemaster 550, a flame retardant mixture)	Cyp1a protein expression	Reduction	Gerlach et al. (2014)
Paclobutrazol (fungicide)	Digestive tract toxicity	Reduction	Wang et al. (2015)
Formylindolo[3,2-b]carbazole (FICZ)	Mortality, pericardial edema, circulatory failure	Prevention	Wincent et al. (2016)
Phenanthroline	PAH-like toxicity	Reduction	Ellis and Crawford (2016)
2,7-Dibromocarbazole and 2,3,6,7-tetrachlorocarbazole	TCDD-like developmental toxicity	Reduction	Fang et al. (2016)
3α,5α-tetrahydrocorticosterone (5α-THB)	Enhanced larval locomotor activity	Blocked enhancement AHR2 knockdown did not block 5β-THB-induced enhanced larval locomotor activity	Wu et al. (2019)
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)	Developmental toxicity (multiple endpoints)	Prevention No change to inhibition of swim bladder inflation and mortality	See text

Measured endpoints that were not altered upon AHR2 knockdown.