Table 2.
Overview of phenotypes from zebrafish triadimefon exposure compared to published in vivo, in vitro data and human studies assessing triazole teratogenicity.
| Phenotype (Identified/Published) | Zebrafish | Mammalian and Other In Vivo Models | In Vitro Models/Embryo Cultures | Human Studies |
|---|---|---|---|---|
| Hatching | Inhibited/delayed: could be a result of decrease movement activity due to somitic abnormalities | |||
| Body length | Shorter: may arise from skeletal defects, irregularities in somitic boundaries and disorganized muscle fibers | Malformations at the level of axial skeleton (FON) [13] Fusions, duplications or morphological transformations of mouse axial segments (FON) [12] Reduced humeral length in mouse (FLUC) [63] Axial skeletal defects in mouse (MIC and MET) [64] Reduced body length in ascidian (IM) [17] | Skeletal defects (FLUC) [60] Skeletal manifestations of humeral radial synostosis and femoral bowing (FLUC) [65] Limb defects (IT) | |
| Spine | Bent: phenotype associated with somitic defects that may lead to muscle and skeletal phenotypes | Axial skeletal and limb defects in mouse (FLUS) [66] Axial skeletal defects in mouse (IT) [67] Limb anomalies in rat (KET) [68] Bent spine in ascidian (IM) [17] Axial defects (homeotic respe-cification/lumbar rib) (FON) [44] Short tail in ascidian (IM, FON) [17] | ||
| Yolk sac | Enlarged/misshaped: associated with lipid metabolism defects | |||
| Swim bladder | Uninflated: secondary effects of the curved spine/muscle/skeletal phenotype, a delay in hatching that didn’t allow inflation to occur on time; reduced movement as a result of somitic defects | |||
| Somites | Irregular somitic formation, disorganized muscle fibers, hypolastic horizontal myoseptum | Somite segmentation defects in X. laevis (FON, NOL) [16] | Fusion of the I and II branchial arches [7] Romboencephalic cleft, abnormal somites (FON) [49] Abnormal somitic develop-ment (KET and EN) [51] | |
| Upper branchial arches (facial structures/mandible/maxillae) | Severely hypoplastic or even absent, Minor delay in development | Micrognathia, microtia, short/fused mandible with zygomatic, joined mandible and maxillae, malformed I and II branchial arches (FON) [13] Abnormal shape, fusions, and agenesis of craniofacial structures originated from branchial ectomesenchyme (palatine, basisphenoid, alisphenoid, pterygoid, squamosal, zygomatic, maxilla, mandible, Meckel’s cartilage, tympanic ring, ear ossicles) during mouse development (FON) [12] Absence of mandibular and maxillary cartilages in X. laevis (FON) [16] Absence of mandibular cartilage and fusion of mandibular cartilage with adjacent structures in X. laevis (NOL) [16] Craniofacial defects in mice (the migration of encephalic neural crest cells) (FON) [44] | Branchial apparatus * reduction/absence, increased cell death of branchial mesenchyme (FLUC and FLU) [50] I branchial arch reduction/I and II branchial arch fusion (FLUC) [57] Reduction of I branchial arch, absence of II branchial arch (FON) [49] Dorso-ventral reduction of I and II branchial arches (NOL) [49] Fusion between I and II branchial arches (FLU, FON and NOL) [69] II branchial arch reduction, I/II branchial arch fusion (KET) [51] I and II branchial arch reduction and fusion (EN) [51] Fusion of the I and II branchial arches (FON) [7] Reduction/ fusion of I and II branchial arches (FON, HEX, FLUS, CYP, MYC, TRI) [70] | |
| Lower branchial arches | Severely hypoplastic hypoplastic or even absent lower pharyngeal arches | Altered morphogenesis of the branchial apparatus (FLUC) [71] II/III branchial arch fusion (KET) [51] | ||
| Clefts | Cleft palate in rat (FLUC, FON, CYP, KET) [12,47,63,68] Cleft palate in mouse (FLUC, IT, FON) [44,45,63,66] | Cleft forebrain and midbrain (KET) [51] | Cleft palate (FLUC) [60,65] Oral cleft (MIC, TER and KET) [59] | |
| Neurocranium | Reduced size/flat forebrain, hypoplastic midbrain, with no clear forebrain midbrain boundaries | Short anterio-dorsal cranial region, slight mouth protrusion of X. laevis (FON, NOL) [16] Alterations of anterior end trunk in ascidian (FON) [17] Abnormal neural crest cell migration from hindbrain to the branchial arches of mice (FLUC) [57] | Reduction of prosencephalon, encephalic schisis (FON) [49] Alterations of hindbrain segmentation (FLU, FON and NOL) [69] Asymmetric forebrain and hindbrain (IMI) [51] Microcephaly, asymmetric forebrain, reduced hindbrain (KET) [51] Reduced, swollen, asymmetric hindbrain (EN) [51] | Craniosynostosis, brachycephaly (FLUC) [60] Craniosynostosis (MIC, TER and KET) [59] Craniosynostosis (FLUC) [65] Craniofacial ossification defects, hypolastic facial bones, small face, brachy-cephaly (FLUC) [60] Microcephalia (IT) |
| Cardiovascular | Pericardial edema, decrease of heart size, linear heart shape/brachycardia, severely decreased or even absent circulation | Cardiac edema of X. laevis (FON, NOL) [16] | Tetralogy of fallot, ventricular septal defects, pulmonary artery hypoplasia (FLUC) [60] Hypoplastic left heart (MIC, TER and KET) [59] Several cardiovascular malformations (FLUC) [65] Hypoplastic left heart syndrome (IT) |
* The branchial apparatus is the embryonic structure that gives rise to embryonic craniofacial structures. CYP, cyproconazole; EN, enilconazole; FLUC, fluconazole; FLUS, flusilazole; FLU, flusinazole; HEX, hexaconazole; IM, imazalil; IMI, imidazole; IT, itraconazole; KET, ketoconazole; MET, metronidazole; MIC, miconazole; MYC, myclobutanil; TER, terconazole; FON, triadimefon; NOL, triadimenol; TRI, triticonazole.