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Evaluating developmental toxicity in the rat as a basis of human risk assessment for cleft palate

Vicario RodrÃguez, Laura

[Thesis]. Manchester, UK: The University of Manchester; 2018.

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Abstract

Cleft palate, one of the most common birth defects worldwide, results from an alteration in the development of the palate, or palatogenesis, which can be caused by multiple genetic or environmental factors. As palatogenesis in humans and mice consists of the same morphological steps, the mouse has been extensively used to study this process. In turn, the rat is the main model to test if a specific substance can cause developmental toxicity symptoms, including cleft palate, as toxic responses in rats can generally be extrapolated to humans. A deeper understanding of the conservation of palatogenesis in mouse and rat could help to evaluate and refine the use of the rat model in human risk assessment studies for clef palate. This situation is addressed in this thesis by employing a new approach based on the comparison of palatogenesis in mouse and rat at the morphological and molecular levels. RNA-seq analysis indicated that most of the mouse and rat orthologues differentially-expressed during palatogenesis displayed similar expression patterns, thus correlating with the morphological similarity of palatogenesis in these species proved by histological analysis. However, the proportion of differentially-expressed genes was greater in mouse. Similarly, when focusing specifically on genes associated with cleft palate, most mouse and rat orthologues were found to have similar RNA-seq expression patterns, although a minor number of potentially relevant differences was identified. Further NanoString and qRT-PCR analyses supported the reproducibility of these results across different mouse and rat biological replicates. In addition, most orthologues analysed by in situ hybridization displayed similar spatial expression patterns in mouse and rat palatal shelves. In conclusion, the results presented in this thesis indicate that palatogenesis is highly conserved in mouse and rat, and support the use of the rat in human risk assessment studies for cleft palate.