Postnatal craniofacial and brain dysmorphology induced by prenatal alcohol exposure in C57BL/6 mouse model

Huisi Ai, Purdue University

Abstract

Purpose: The objective is to evaluate postnatal craniofacial bone and brain dysmorphology induced by prenatal alcohol exposure with different doses and stages and nutrition deficits by applying multi-modality imaging techniques including micro-CT, quantitative CT and preclinical MRI on FASD mouse model. Materials and Methods: C57BL/6J female mice were divided into three treated groups, ALC (pre- and pregnancy alcohol with 4.2% v/v or 3.6% v/v (liquid diet with high or low dose alcohol)), PF (pre alcohol and a calorically matched liquid pregnancy diet), and CHOW (ad lib chow/water). The pregnancy exposure lasted from embryonic day (E) 7 - E16 (long exposure) or from E7 - E11 (short exposure). All delivered pups were culled to 6/litter and surrogate fostered. For all the mouse pups treated with two doses and two stages of prenatal alcohol exposure, craniofacial bones were imaged using 3D micro-CT. Thirteen craniofacial morphometric measurements from bone landmarks were defined and examined by ANOVA and logistic regression to discern features associated with prenatal alcohol exposure or nutrition deficits with high accuracy. For mice treated with high dose long exposure alcohol, three neurocranial and two viscerocranial bones were segmented from CT images to investigate alcohol-induced bone growth retardation by performing volumetric analysis using general linear model. In addition, preclinical MR imaging was performed on mouse samples treated with high dose long exposure to assess brain structure abnormalities. Finally, Pearson correlation analysis was applied to connect craniofacial measures with certain brain measures. Results: For craniofacial morphometric measures, lower dose alcohol treatment showed more acute effect while higher dose showed more longitudinal effect. Short exposure treatment showed minimal impact on morphometric measures at both P7 and P21 comparing with long exposure treatment. Combination of alcohol exposure and nutrition deficits had significant and long-lasting impact on craniofacial features. Nutritional factor along can also cause craniofacial dysmorphology. The neurocranial bones were significantly affected by high dose long exposure alcohol treatment to a greater degree than the viscerocranial bones. Moreover, prenatal alcohol exposure caused significant bone mineral density loss on mouse skull. High field preclinical MRI scanner showed good image quality to detect alcohol-induced brain structure anomalies. High dose long exposure alcohol treatment caused significant volume reductions in whole brain volume, olfactory bulb, cerebellum and septum volumes comparing with non-alcohol treated group. Finally, a group of craniofacial morphometric measures were demonstrated with significant correlation with certain brain linear and volumetric measures. Conclusion: This study demonstrated the feasibility of multi-modality imaging techniques to evaluate alcohol-induced teratogenesis in craniofacial bone and brain using mouse model. The results were valuable in better understanding alcohol dose and stage dependency of craniofacial bone and brain structural abnormalities and improvement of FASD diagnosis.

Degree

Ph.D.

Advisors

Liang, Purdue University.

Subject Area

Medical imaging

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