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Pathogenesis of craniofacial and body wall malformations induced by ochratoxin A in mice
Abstract:
Ochratoxin A (OA), a mycotoxin commonly found in soils and on moldy food such as cereal grains, is a potent teratogen. The present investigation was designed to examine the teratogenicity of OA administered acutely at early post-implantation stages in mice, with particular emphasis on the pathogenetic basis of induced malformations. Maternal OA administration on gestational day (GD) 7 or 8 resulted in excessive amounts of cell death in selected cell populations. After a single dose of 2-4 mg/kg, excessive cell death was notable within 6 hours, and persisted to 36 hours post-treatment. As observed in GD 14 or 18 fetuses, the spectrum of induced craniofacial malformations included exencephaly, midfacial clefting, cleft lip, as well as hypotelorism, and synophthalmia associated with holoprosencephaly. Body wall defects involved either the abdominal wall alone, or in combination with the thoracic wall, resulting in partial or complete exposure of the viscera. Potential mechanisms for OA-induced selective cell killing are discussed.
Insights
Ochratoxin A (OA) exposure during early pregnancy causes significant cell death and severe birth defects in mice, including craniofacial and body wall malformations. This study investigates the teratogenic effects and underlying mechanisms of OA.
Area of Science:
- Toxicology
- Developmental Biology
- Teratology
Background:
- Ochratoxin A (OA) is a prevalent mycotoxin found in food and soil.
- OA is recognized as a potent teratogen, posing risks to embryonic development.
Purpose of the Study:
- To investigate the teratogenicity of acute Ochratoxin A exposure in mice during early post-implantation stages.
- To elucidate the pathogenetic basis of OA-induced malformations, focusing on cellular mechanisms.
Main Methods:
- Mice were administered a single dose of Ochratoxin A (2-4 mg/kg) on gestational days 7 or 8.
- Embryonic and fetal development was assessed, with examination of malformations on gestational days 14 or 18.
- Cell death in specific embryonic populations was quantified at various time points post-treatment.
Main Results:
- Acute OA exposure induced widespread cell death in critical embryonic cell populations within 6-36 hours.
- Significant craniofacial defects were observed, including exencephaly, midfacial clefting, cleft lip, hypotelorism, and synophthalmia.
- Body wall defects, such as abdominal and thoracic wall defects leading to visceral exposure, were also induced.
Conclusions:
- Ochratoxin A is a potent teratogen that causes severe developmental abnormalities in mice through selective cell killing.
- The timing of OA exposure during early gestation is critical for the induction of specific malformations.
- Understanding OA's mechanisms of teratogenicity is crucial for assessing human health risks associated with mycotoxin exposure.