Peripheral RNA Biomarkers for Neurocognitive Impairment in the Mouse Models of Offspring from Mother with Diabetes

Diabetes during gestation negatively correlates with cognitive and behavioral functions of the child. To better understand the correlation, we aim at defining peripheral biomarkers of cognitive impairment in offspring from mother with diabetes (OMD). As the first step, we established mouse model of OMD. Six weeks old CD-1 female mice received intraperitoneal (i.p.) injection of streptozotocin (STZ) (150mg/kg). Following confirmation of diabetes 2 weeks post STZ injection, these animals were crossed with normal male to give OMD. The accelerated rotarod test was performed on OMD (n=26) and the control animals (n=30) at postnatal day 30-31. OMD shows impaired motor skill learning (p<0.05). From OMD and the control animals, three subtypes (T cell, B cell and monocytes) of white blood cells were sorted by using Flow cytometer for RNA sequencing. We performed both differential expression and splicing analyses. Interestingly, by comparing another mouse offspring model of fetal stress exposure, fetal alcohol spectrum disorders (FASD) model, offspring from dam received i.p. injections of 25% ethanol at 4.0 g/kg daily at embryonic day 16-17, that shows the same motor skill learning deficits, we found that common differential alternative splicing events between OMD and FASD. 13, 16, and 0 alternative splicing events are defined in T cell, B cell and monocytes respectively. In contrast, there are very few common differential gene expressions. Deep learning with those common alternative splicing biomarkers in T cell gave ∼0.8 accuracy in classification of good and poor learners. Collectively, these results demonstrate potential of the alternative splicing events as the biomarkers of cognitive impairment in OMD. Disclosure J. Sasaki: None. D. Dutta: None. K. Sugai: None. T. Sasaki: None. A. Bansal: None. S. Yamashita: None. M. Odawara: Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Other Relationship; Self; Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo, Eli Lilly Japan K.K., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. M. Torii: None. K. Hashimoto-Torii: None. Funding National Institutes of Health (UH2AA026106)