Abstract
AimTo characterize the abnormal metabolic profile of all-trans-retinoic acid (ATRA)–induced craniofacial development in mouse embryos using proton magnetic resonance spectroscopy (1H-MRS).MethodsTimed-pregnant mice were treated by oral gavage on the morning of embryonic gestation day 11 (E11) with all-trans-retinoic acid (ATRA). Dosing solutions were adjusted by maternal body weight to provide 30, 70, or 100 mg/kg RA. The control group was given an equivalent volume of the carrier alone. Using an Agilent 7.0 T MR system and a combination of surface coil coils, a 3 mm×3 mm×3 mm 1H-MRS voxel was selected along the embryonic craniofacial tissue. 1H-MRS was performed with a single-voxel method using PRESS sequence and analyzed using LCModel software. Hematoxylin and eosin was used to detect and confirm cleft palate.Result 1H-MRS revealed elevated choline levels in embryonic craniofacial tissue in the RA70 and RA100 groups compared to controls (P<0.05). Increased choline levels were also found in the RA70 and RA100 groups compared with the RA30 group (P<0.01). High intra-myocellular lipids at 1.30 ppm (IMCL13) in the RA100 group compared to the RA30 group were found (P<0.01). There were no significant changes in taurine, intra-myocellular lipids at 2.10 ppm (IMCL21), and extra-myocellular lipids at 2.30 ppm (EMCL23). Cleft palate formation was observed in all fetuses carried by mice administered 70 and 100 mg/kg RA.ConclusionsThis novel study suggests that the elevated choline and lipid levels found by 1H-MRS may represent early biomarkers of craniofacial defects. Further studies will determine performance of this test and pathogenetic mechanisms of craniofacial malformation.
Highlights
Craniofacial morphogenesis, an intricate developmental process, begins with the synchronized development of head primordia, which involves several organizing centers located in the neural ectoderm, axial mesendoderm, and the cranial neural crest [1]
This novel study suggests that the elevated choline and lipid levels found by 1H-MRS may represent early biomarkers of craniofacial defects
The analyses demonstrated the relationship between the changes in endogenous small molecular metabolites of the craniofacial structure and the incidence of cleft palate in embryos
Summary
Craniofacial morphogenesis, an intricate developmental process, begins with the synchronized development of head primordia, which involves several organizing centers located in the neural ectoderm, axial mesendoderm, and the cranial neural crest [1]. Environmental insults, or the combination of both can result in craniofacial malformations [3]. Craniofacial malformations are involved in three fourths of all congenital birth defects in humans [2]. Cleft lip and palate (CLP) is the most common birth defect in human craniofacial development, causes considerable morbidity to affected children, and imposes a substantial financial risk and a concomitant societal burden for families [4]. Maternal conditions during pregnancy appear to play an important role in the formation of CLP, and vitamin deficiency and teratogens may increase risk for oral clefts [7,8,9]
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