DNA damage and DNA damage response (DDR) in neurulation stage embryos under maternal diabetes conditions are not well understood. The purpose of this study was to investigate whether maternal diabetes and high glucose in vitro induce DNA damage and DDR in the developing embryo through oxidative stress. In vivo experiments were conducted by mating superoxide dismutase 1 (SOD1) transgenic male mice with wild-type (WT) female mice with or without diabetes. Embryonic day 8.75 (E8.75) embryos were tested for the DNA damage markers, phosphorylated histone H2A.X (p-H2A.X) and DDR signaling intermediates, including phosphorylated checkpoint 1 (p-Chk1), phosphorylated checkpoint 2 (p-Chk2), and p53. Levels of the same DNA damage markers and DDR signaling intermediates were also determined in the mouse C17.2 neural stem cell line. Maternal diabetes and high glucose in vitro significantly increased the levels of p-H2A.X. Levels of p-Chk1, p-Chk2, and p53, were elevated under both maternal diabetic and high glucose conditions. SOD1 overexpression blocked maternal diabetes-induced DNA damage and DDR in vivo. Tempol, a SOD1 mimetic, diminished high glucose-induced DNA damage and DDR in vitro. In conclusion, maternal diabetes and high glucose in vitro induce DNA damage and activates DDR through oxidative stress, which may contribute to the pathogenesis of diabetes-associated embryopathy.

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METHODS: Hemicastration was performed in C57BL/6 mice at a neonatal, prepubertal or postpubertal period between days of life (DOL) 2-4, 20-22 and 42-44, respectively. These mice and a control group whom did not undergo a procedure were sacrificed after physical maturity (DOL 80) and remaining testis was removed. We evaluated FSH levels, histology, body weight (BW), testis weight (TW) and testis long-axis (calipers). The larger testis was recorded for controls. ANOVA was used to determine statistical significance (p<0.05).RESULTS: Median neonatal and prepubertal TW were significantly greater than control; however, only the median TW/BW ratio in the neonatal group was significantly higher than control, implying the greatest degree of compensatory growth happened with earlier testis loss. Neonatal TW was also significantly greater than postpubertal TW. No difference in BW or testis long axis length in any group was detected (Figure 1). H&E evaluation showed similar degree of spermatogenesis and Leydig cell concentration among all mice. Mean FSH (ng/mL) was highest in postpubertal (105.9) followed by prepubertal (98.5), neonate (93.9) and control (61.2), suggesting lower global sperm production in mice with testis loss at a later age.CONCLUSIONS: Contralateral testicular hypertrophy occurred if testis loss was during the prepubertal period and our data implies that earlier testis loss may have a greater degree of compensation and maintained reproductive function. This challenges the notion that the testis remains quiescent during childhood as there must be a signaling cascade to promote testicular hypertrophy. To our knowledge, this is the first study to successfully perform hemicastration in neonatal mice. This model will be used to study molecular mechanisms that influence testicular growth after unilateral testis loss .

We present a very rare Case of a 53-year-old female with autosomal dominant polycystic kidney disease (ADPKD) who was incidentally found to have a reno-appendiceal fistula while undergoing open bilateral nephrectomy. The mid-portion of the appendix was fistulized to a cyst in the lower pole of the right kidney. The etiology was likely due to chronic inflammation. An appendectomy was performed along with the planned right nephrectomy to ensure complete removal of the fistulous tract.