Supplementary MaterialsSupplementary Results. even low levels of radiation can increase the

Supplementary MaterialsSupplementary Results. even low levels of radiation can increase the risk of fetal damage. The incidence of miscarriage, preterm delivery and death during infancy are more common in pregnant women exposed to radiation. However, there are medical situations where pregnant women are intentionally exposed to radiation due to life-threatening conditions. The number of pregnant women undergoing computed tomography (CT) imaging, which delivers more radiation than other radiologic procedures, has nearly doubled in the past decade.1 To date, shielding has been the only method for protecting the RAD001 cost fetus against radiation injury. Nuclear accidents or terrorism can also place the fetus at significant risk. Purinergic receptors are a family of transmembrane proteins that is activated by nucleosides, nucleotides, and nucleotide sugars. Purinergic receptors are divided into P1 adenosine receptor, P2X ionotropic receptor and P2Y metabotropic receptor.2, KIT 3 Purines and pyrimidines are massively released at the site of damage resulting from irradiation (IR), stress, or hypoxia and trigger the activation of purinergic signaling pathways.4, 5 Activation of these receptors serves as a sensor and responder to damage-induced alarm signals and has an important role in modulating tissue homeostasis under stress.6 Most of the purinergic receptor knockout (KO) mice, including A2?A, P2Y4, and P2Y2, display no overt phenotype under homeostatic conditions, but knockdown phenotypes become apparent when KO mice are exposed to stresses or stimuli.7, 8 This indicates that the functional role of purinergic receptors is more apparent under pathophysiological conditions than under homeostatic conditions. Meanwhile, Wells IR. Results Under homeostatic conditions, heterozygous (+/?) and homozygous (?/?) mice have normal growth and fertility and exhibit no apparent phenotypic abnormalities. As purinergic receptor signaling is often associated with cellular responses to tissue injury,5 we investigated the potential role of P2Y14 RAD001 cost to protect cells from genotoxic injury induced by IR. We focus here on the impact of P2Y14 on developing embryos, as embryos are highly vulnerable to IR-induced damage and radiation exposure can have profound health consequences later in life. Heterozygous females were mated with heterozygous males. On day 11.5 of pregnancy (E11.5), pregnant females were exposed to total-body irradiation (TBI). Pregnant mice were exposed to various IR regimens. It has been previously shown that doses higher than 1.9?Gy (TBI) lead to embryonic death12 and we also found that at a dose of 2?Gy TBI none of the P2Y14 embryos, regardless of their genotypes, were able to survive to birth. A dose of 1 1.5?Gy TBI was the maximum dose at which the three mouse genotypes were born at the expected Mendelian ratio without significantly affecting litter size (see Supplementary Results). The litters born to radiation-treated dams did not display any apparent developmental abnormalities and were phenotypically indistinguishable between genotypes during the postnatal period. Litter weights at birth and 3 weeks of age were also not significantly different between genotypes (see Supplementary Results). However, beginning around puberty (between 4 and 6 weeks of age), the majority of irradiated wild-type mice began to show retarded growth and weight gain (Figures 1a and b). These mice became moribund and approximately 70C75% of WT offspring died as they reached RAD001 cost puberty (Figure 1c). In contrast, a significantly higher percentage of irradiated P2Y14 homozygous (irradiated embryos. (a) Body weight of littermates was measured on a weekly basis. With the onset of puberty, the growth rate of WT offspring (white triangles) was significantly retarded compared with KO (white gemstones) as well as UDP-Glc-treated WT offspring (black triangles). In comparison to P2Y14 offspring created to dams who have been never exposed to prenatal irradiation (observe red dashed collection), the offspring created to irradiated dams, regardless of genotype, showed a tendency toward slightly lower body weights. As body weight can be affected by postmortem dehydration, the results of deceased animals were not included in data collection (irradiated offspring. WT offspring (white triangles) showed a notably improved incidence of postpubertal mortality as compared with KO (white gemstones) and UDP-Glc-treated WT offspring (black triangles). irradiated WT offspring (Numbers 1a and b). UDP-Glc treatment also significantly enhanced postpubertal survival of irradiated WT offspring (Number 1c). This is to some extent surprising, as deficiency of P2Y14 receptor endowed offspring with.