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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 271 records · Page 15
All sourcesNASA NTRSDOE OSTI
DOE OSTI2015

Evaluate an impact of incident alpha particle and gamma ray on human blood components: A comparison study

An impact of alpha and gamma irradiation on human blood components have been evaluated and compared for healthy blood samples (male and females). Irradiation dose and time of irradiation calibrated and considered as a main comparison factors. Density of blood components measured for each in vitro irradiation before and after irradiation for males and females. Survey radiation dosimeter (Inspector Exp) and nuclear track detectors type CR-39 used to evaluate exposure dose rate and incident density of alpha particles, respectively. Experiment results verified that the irradiation of blood makes ionizing of blood components, either alpha or gamma irradiation dose, and the impacts of ionizing radiation were relativity for WBC, RBC, and PLT. Limited irradiation doses of 1-5 μSv/hr considered as a low radiation dose of alpha and gamma radiation sources ({sup 226}Ra, and {sup 137}Cs). Density of alpha particles accumulated on the blood surface was 34 (alpha particle/cm{sup 2}) for selected dose of incident alpha particle. Optimum value of irradiation dose and time of irradiation were 5 μSv/hr and 4 second for males and females. On the other hands, the values of irradiation dose and time of irradiation were 2.1 μSv/hr and 2 second for males and females for gamma irradiation. Thus, present results demonstrated that densities of RBC and WBC cells are capable of inducing reproduction in vitro for both type of irradiation. (authors)

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗
DOE OSTI2022

Determination and analysis of sex ratios in heme oxygenase 1 gene targeted mouse embryos

Abstract Heme oxygenase 1 or Hmox1 enzyme is involved in catalyzing the first and rate‐limiting step in heme breakdown reactions. Many studies have reported a partial lethality of Hmox1 knockout mice obtained from heterozygous breeding pairs. Similar results were obtained in our transgenic mice colony and a sex specific bias was observed in the favor of males in the adult mice. Hmox1 independent factors which could have caused this bias were initially analyzed and it was found that those factors were not a reason behind this anomaly. Certain studies involving gene knockout hinted toward a prenatal or neonatal lethality of female knockout mice embryos or pups, respectively. In order to check if this bias was occurring in embryonic stages, that is, either if mutant female embryos were dying or if heterozygous mothers were not carrying embryos to term, we analyzed the sex‐ratios in mid‐ and late‐gestational ages (9.5–13.5 dpc and 14.5–18.5 dpc, respectively). Our results did not indicate any significant difference in the sex ratios in embryonic stages; hence, it was concluded that females are not dying in embryonic stages. It can be speculated that these deaths were probably occurring at neonatal age. More studies are required to confirm that the lack of Hmox1 gene products is the sole reason for this female lethality.

Jain, Sidhant↗
DOE OSTI2023

Obesity is associated with biliary tract cancer mortality and incidence: A pooled analysis of 21 cohort studies in the Asia Cohort Consortium

Abstract Body fatness is considered a probable risk factor for biliary tract cancer (BTC), whereas cholelithiasis is an established factor. Nevertheless, although obesity is an established risk factor for cholelithiasis, previous studies of the association of body mass index (BMI) and BTC did not take the effect of cholelithiasis fully into account. To better understand the effect of BMI on BTC, we conducted a pooled analysis using population‐based cohort studies in Asians. In total, 905 530 subjects from 21 cohort studies participating in the Asia Cohort Consortium were included. BMI was categorized into four groups: underweight (<18.5 kg/m 2 ); normal (18.5‐22.9 kg/m 2 ); overweight (23‐24.9 kg/m 2 ); and obese (25+ kg/m 2 ). The association between BMI and BTC incidence and mortality was assessed using hazard ratios (HR) and 95% confidence intervals (CIs) by Cox regression models with shared frailty. Mediation analysis was used to decompose the association into a direct and an indirect (mediated) effect. Compared to normal BMI, high BMI was associated with BTC mortality (HR 1.19 [CI 1.02‐1.38] for males, HR 1.30 [1.14‐1.49] for females). Cholelithiasis had significant interaction with BMI on BTC risk. BMI was associated with BTC risk directly and through cholelithiasis in females, whereas the association was unclear in males. When cholelithiasis was present, BMI was not associated with BTC death in either males or females. BMI was associated with BTC death among females without cholelithiasis. This study suggests BMI is associated with BTC mortality in Asians. Cholelithiasis appears to contribute to the association; and moreover, obesity appears to increase BTC risk without cholelithiasis.

Oze, Isao↗
DOE OSTI2020

The role of mab‐3 in spermatogenesis and ontogenesis of pinewood nematode, Bursaphelenchus xylophilus

Abstract Background Bursaphelenchus xylophilus is one of the most destructive invasive species, causing extensive economic losses worldwide. The sex ratio of female to male of B. xylophilus plays an important role in the nematode infestation. However, little is known about the processes of its sex determination. The double sex/mab‐3‐related family of transcription factors are highly conserved in animals, playing crucial roles in sex determination, spermatogenesis and ontogenesis. We therefore investigated its orthologue, Bxy‐mab‐3 , in B. xylophilus . Results Bxy‐mab‐3 has two typical conserved DNA‐binding domains. It was observed in J2 (the second‐stage of juveniles), J3, J4 and male adults (specifically on the spicules), but not in eggs or female adults via mRNA in situ hybridization. RNA‐Seq indicated significantly higher expression in males. RNAi showed that the body size and sperm size of male adults were markedly smaller than those of the controls. Meanwhile, almost all the RNAi‐treated males failed to mate with the normal females, even 26.34% of interfered males did not produce sperm. However, RNAi of Bxy‐mab‐3 had no effect on the sex ratio of B. xylophilus . Conclusion Bxy‐mab‐3 is indispensable for spermatogenesis, ontogenesis and mating behavior. It is a typical sex‐determination gene with differential expression in males and females. However, knocking down Bxy‐mab‐3 expression could not alter the sex ratio as seen in other species. Our findings contribute towards a better understanding of the molecular events of Bxy‐mab‐3 in B. xylophilus , which provides promising hints for control of pine wilt disease by blocking ontogenesis and decreasing nematode fecundity.

Zhou, Lifeng↗
DOE OSTI2019

Establishing a Platform for Interest and Education in Interventional Radiology Amongst Radiology Trainees

Purpose: Over recent times, procedural Radiologists have begun to establish themselves as the distinct subspecialty of Interventional Radiology (IR). The Interventional Radiology Society of Australasia (IRSA) was established in 1982 to share collaborative ideas, encourage research, and promote education. IRSA developed a weekend registrar workshop attended by Radiology Registrars from Australia and New Zealand. In the 2018 event, we surveyed the Registrars to identify their interest in IR training before and after the workshop. Materials and Methods: The event was held over a weekend and consisted of both lectures and hands-on workshops. A survey was handed to all 67 registrants of the workshop and there was a 55% response rate including 78% of females in attendance. Results: Before the workshop, trainees rated their interest in IR training at a mean of 3.7 out of 5. After the workshop, trainees rated their interest in IR training as an average of 4.4 out of 5 (p < 0.001). The difference in interest between males and females before the workshop (4.0 vs. 3.1) was significant (p = 0.003), however after the workshop (4.5 vs. 4.1) was not significant (p = 0.07). The change in interest from attending the workshop was significant between genders, p = 0.03 (male interest increased mean 0.5, female increased mean 1.0). Conclusion: We show that a program of lectures and workshops designed to generate interest in IR leads to a significant increase in training interest, particularly amongst females. Other subspecialty groups should consider this type of intervention and promote ongoing education and inspiration. Level of Evidence: Cross-sectional study, Level IV.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

High-Grade Vulvar, Vaginal, and Anal Precancers Among U.S. Adolescents and Young Adults After Human Papillomavirus Vaccine Introduction

Since human papillomavirus vaccine introduction, incidence rates of cervical precancers have decreased; however, the vaccine's impact on noncervical anogenital precancers has not been shown. These precancers are identified opportunistically and are not collected routinely by most cancer registries. This study examined the incidence rates of high-grade (intraepithelial lesions grade 3) vulvar, vaginal, and anal precancers among persons aged 15–39 years using 2000–2017 data from select cancer registries covering 27.8% of the U.S. population that required reporting of these precancers. Trends in incidence rates were evaluated with Joinpoint regression. Analyses were conducted in 2020. High-grade vulvar precancer rates declined by 21.0% per year after human papillomavirus vaccine introduction among females aged 15–19 years. In addition, high-grade vaginal precancer rates declined by 19.1% per year among females aged 15–29 years after human papillomavirus vaccine introduction. Compared with that in the prevaccine period when high-grade anal precancer rates were increasing, anal precancer rates after human papillomavirus vaccine introduction were stable among females aged 15–29 years and among males aged 30–39 years. Among males aged 15–29 years, the rates increased over the entire period but less so after human papillomavirus vaccine introduction. In conclusion, opportunistically-detected high-grade vulvar and vaginal precancers among females aged 15–29 years decreased and anal precancers stabilized in years after the introduction of the human papillomavirus vaccine, which is suggestive of the impact of the vaccine on noncervical human papillomavirus cancers.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2026

Temporal multi-omic analysis uncovers sex-biased molecular programs underlying skeletal muscle adaptation to endurance training

Background. Exercise training is known to benefit health and reduce disease risk. While adaptations in skeletal muscles are fundamental to many of the health benefits of exercise training, the common and sex-specific molecular regulators that mediate these adaptations remain to be fully elucidated. Methods. To this end, we leveraged skeletal muscle multi-omics data generated by the Molecular Transducers of Physical Activity Consortium (MoTrPAC), where 6 month-old male and female rats endurance trained for 1, 2, 4, or 8 weeks. Our objective was to identify shared and sex-specific multi-omic molecular responses to endurance training in skeletal muscle, and relate them to phenotypic adaptations. Results. We identified largely sexually-conserved transcriptomic and proteomic enrichments in the gastrocnemius, which correlated with skeletal muscle responses from a published exercise study in humans. We uncovered sex-consistent post-translational modifications, including decreased oxidation of MYH2 and deacetylation of the ß-oxidation enzyme HADHA. Pathway enrichment analyses revealed sex-specific remodeling across the acetylome, redox proteome, and phosphoproteome; females decreased mitochondrial protein oxidation and increased mitochondrial cristae proteins, indicative of enhanced redox buffering and mitochondrial efficiency. Despite observed decreases in the oxidation of key mitochondrial proteins, females displayed increases in the oxidation of proteins involved in glucose catabolism relative to males after 8 weeks of training, suggestive of sex-biased subcellular reactive oxygen species generation. Conclusions. This work shows a large portion of the adaptive response to endurance training in skeletal muscle is shared between females and males, while there are distinct and nuanced sex-specific adaptations that are evident, particularly at the level of post-translational regulation.

Many, Gina M.↗
DOE OSTI2015

Maternal blood metal levels and fetal markers of metabolic function

Exposure to metals commonly found in the environment has been hypothesized to be associated with measures of fetal growth but the epidemiological literature is limited. The Maternal–Infant Research on Environmental Chemicals (MIREC) study recruited 2001 women during the first trimester of pregnancy from 10 Canadian sites. Our objective was to assess the association between prenatal exposure to metals (lead, arsenic, cadmium, and mercury) and fetal metabolic function. Average maternal metal concentrations in 1st and 3rd trimester blood samples were used to represent prenatal metals exposure. Leptin and adiponectin were measured in 1363 cord blood samples and served as markers of fetal metabolic function. Polytomous logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between metals and both high (≥90%) and low (≤10%) fetal adiponectin and leptin levels. Leptin levels were significantly higher in female infants compared to males. A significant relationship between maternal blood cadmium and odds of high leptin was observed among males but not females in adjusted models. When adjusting for birth weight z-score, lead was associated with an increased odd of high leptin. No other significant associations were found at the top or bottom 10th percentile in either leptin or adiponectin models. This study supports the proposition that maternal levels of cadmium influence cord blood adipokine levels in a sex-dependent manner. Further investigation is required to confirm these findings and to determine how such findings at birth will translate into childhood anthropometric measures. - Highlights: • We determined relationships between maternal metal levels and cord blood adipokines. • Cord blood leptin levels were higher among female than male infants. • Maternal cadmium was associated with elevated leptin in male, not female infants. • No significant associations were observed between metals and cord blood adiponectin. • Further work will elucidate the implications of these findings on childhood obesity.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2015

Infant sex-specific placental cadmium and DNA methylation associations

Background: Recent evidence suggests that maternal cadmium (Cd) burden and fetal growth associations may vary by fetal sex. However, mechanisms contributing to these differences are unknown. Objectives: Among 24 maternal-infant pairs, we investigated infant sex-specific associations between placental Cd and placental genome-wide DNA methylation. Methods: We used ANOVA models to examine sex-stratified associations of placental Cd (dichotomized into high/low Cd using sex-specific Cd median cutoffs) with DNA methylation at each cytosine-phosphate-guanine site or region. Statistical significance was defined using a false discovery rate cutoff (<0.10). Results: Medians of placental Cd among females and males were 5 and 2 ng/g, respectively. Among females, three sites (near ADP-ribosylation factor-like 9 (ARL9), siah E3 ubiquitin protein ligase family member 3 (SIAH3), and heparin sulfate (glucosamine) 3-O-sulfotransferase 4 (HS3ST4) and one region on chromosome 7 (including carnitine O-octanoyltransferase (CROT) and TP5S target 1 (TP53TG1)) were hypomethylated in high Cd placentas. Among males, high placental Cd was associated with methylation of three sites, two (hypomethylated) near MDS1 and EVI1 complex locus (MECOM) and one (hypermethylated) near spalt-like transcription factor 1 (SALL1), and two regions (both hypomethylated, one on chromosome 3 including MECOM and another on chromosome 8 including rho guanine nucleotide exchange factor (GEF) 10 (ARHGEF10). Differentially methylated sites were at or close to transcription start sites of genes involved in cell damage response (SIAH3, HS3ST4, TP53TG1) in females and cell differentiation, angiogenesis and organ development (MECOM, SALL1) in males. Conclusions: Our preliminary study supports infant sex-specific placental Cd-DNA methylation associations, possibly accounting for previously reported differences in Cd-fetal growth associations across fetal sex. Larger studies are needed to replicate and extend these findings. Such investigations may further our understanding of epigenetic mechanisms underlying maternal Cd burden with suboptimal fetal growth associations. - Highlights: • We examine sex-specific placental-Cd and -genome-wide DNA methylation associations. • In females, associated sites were at/near genes involved in cell damage response. • In males, associated sites were at/near angiogenesis and organ development genes. • Our study supports infant sex-specific placental Cd-DNA methylation associations.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Urinary phthalate metabolites and environmental phenols in university students in South China

Highlights: • University students in South China might be exposed to higher levels of phthalates than parabens or bisphenol analogues. • Concentrations of target EEDs were relatively low in university students, with higher levels in female than male students. • The usage of PCPs is an important source other than diet to affect the profiles of phthalates and parabens in students. In China, university students have unique lifestyles compared with the rest of the youth population, as they are almost entirely isolated in campuses. The number of university students is large, and since students represent the future of human reproduction, exposure to environmental endocrine disruptors (EEDs) may have a large impact on society. In this study, levels of several EEDs, including phthalate metabolites, parabens, bisphenol A (BPA) and its analogues, triclosan (TCS), and benzophenone-3, were determined in 169 urine samples collected from university students in Guangzhou, South China. In addition, to further understand the potential sources of EEDs in their daily lives, a survey of students’ lifestyles was conducted. Based on the urinary concentrations of EEDs and the survey results, daily exposure doses of target EEDs and their potential sources were investigated. Our results indicated that nine phthalate metabolites, three parabens, and BPA were ubiquitous (detection frequency > 60%) in the urine of university students. The concentrations of total phthalates (median: 99.4 µg L{sup −1}) were orders of magnitude higher than those of total parabens (7.30 µg L{sup −1}) and of other environmental phenols (0.40 µg L{sup −1}). Significantly higher concentrations of phthalates, parabens, and TCS were found in female versus male students, partly due to the higher usage of personal care products (PCPs) by female students (p < 0.05). The estimated daily intakes (EDIs) of phthalates, parabens, BPA, and TCS were 0.46–1.35, 3.29–10.3, 0.007, and 0.67 µg/kg-bw/day, respectively. The EDIs of phthalates and BPA were much lower than those suggested by the European Food Safety guidelines (10, 50, and 50 µg/kg-bw/day for dibutyl phthalate, diethylhexyl phthalate, and BPA, respectively). Our results indicated that university students were widely exposed to EEDs, but at relatively low doses. PCP usage was the main reason for differences in levels of phthalates (especially diethyl phthalate) and parabens between male and female students in South Chinese universities.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Effects of biometrics, location and persistent organic pollutants on blood clinical-chemical parameters in polar bears (Ursus maritimus) from Svalbard, Norway

Highlights: • BCCPs in polar bears may be affected by sex, age, biometrics, lipids and location. • POPs were correlated with HCT and HDL in females, and HCT, GGT, ASAT and CHOL in males. • POPs related biological effects on liver and kidney BCCP values were suggested. • HCT may be used as a simple cost-efficient biomarker of POP exposure in polar bears. • POPs effects on HDL and CHOL may indicate increased risk of cardiovascular disease in polar bears. In the present study, blood clinical-chemical parameters (BCCPs) were analysed in 20 female and 18 male Svalbard polar bears (Ursus maritimus) captured in spring 2007. The aim was to study how age, body condition (BC), biometrics, plasma lipid content and geographical location may confound the relationship between persistent organic pollutants (POPs) including PCBs, HCB, chlordanes, DDTs, HCHs, mirex and OH-PCBs and the concentrations of 12 specific BCCPs (hematocrit [HCT], hemoglobin [HB], aspartate aminotransferase [ASAT], alanine aminotransferase [ALAT], γ-glutamyltransferase [GGT], creatine kinase [CK], triglycerides [TG], cholesterol [CHOL], high-density lipoprotein [HDL], creatinine (CREA], urea, potassium (K]), and to investigate if any of these BCCPs may be applied as potential biomarkers for POP exposure in polar bears. Initial PCA and O-PLS modelling showed that age, lipids, BC and geographical location (longitude and latitude) were important parameters explaining BCCPs in females. Following subsequent partial correlation analyses correcting for age and lipids, multiple POPs in females were still significantly correlated with HCT and HDL (all p < 0.05). In males, age, BM, BC and longitude were important parameters explaining BCCPs. Following partial correlation analyses correcting for age, biometrics, lipids and longitude in males, multiple POPs were significantly correlated with HCT, ASAT, GGT and CHOL (all p < 0.05). In conclusion, several confounding parameters has to be taken into account when studying the relations between BCCPs and POPs in polar bears. When correcting for these, in particular HCT may be used as a simple cost-efficient biomarker of POP exposure in polar bears. Furthermore, decreasing HDL concentrations and increasing CHOL concentration with increasing POP concentrations may indicate responses related to increased risk of cardiovascular disease. We therefore suggest to further study POP exposure and lipidome response to increase knowledge of the risk of cardiometabolic syndrome in polar bears.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2016

Factors Affecting Gender-based Experiences for Residents in Radiation Oncology

Purpose: Although women constitute approximately half of medical school graduates, an uneven gender distribution exists among many specialties, including radiation oncology, where women fill only one third of residency positions. Although multiple social and societal factors have been theorized, a structured review of radiation oncology resident experiences has yet to be performed. Methods and Materials: An anonymous and voluntary survey was sent to 611 radiation oncology residents practicing in the United States. Residents were asked about their gender-based experiences in terms of mentorship, their professional and learning environment, and their partnerships and personal life. Results: A total of 203 participants submitted completed survey responses. Fifty-seven percent of respondents were men, and 43% were women, with a mean age of 31 years (standard deviation=3.7 years). Although residents in general value having a mentor, female residents prefer mentors of the same gender (P<.001), and noted having more difficulty finding a mentor (P=.042). Women were more likely to say that they have observed preferential treatment based on gender (P≤.001), and they were more likely to perceive gender-specific biases or obstacles in their professional and learning environment (P<.001). Women selected residency programs based on gender ratios (P<.001), and female residents preferred to see equal numbers of male and female faculty (P<.001). Women were also more likely to perceive work-related strain than their male counterparts (P<.001). Conclusions: Differences in experiences for male and female radiation oncology residents exist with regard to mentorship and in their professional and learning environment.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2017

In vitro metabolism of benzo[a]pyrene-7,8-dihydrodiol and dibenzo[def,p]chrysene-11,12 diol in rodent and human hepatic microsomes

Polycyclic aromatic hydrocarbons (PAHs) are contaminants that are ubiquitously found in the environment, produced through combustion of organic matter or petrochemicals, and many of which are procarcinogens. The prototypic PAH, benzo[a]pyrene (B[a]P) and the highly carcinogenic dibenzo[def,p]chrysene (DBC) are metabolically activated by isoforms of the P450 enzyme superfamily producing benzo[a]pyrene-7,8-dihydrodiol (B[a]P diol), dibenzo[def,p]chrysene-11,12 diol (DBC diol). Each of these diols can be further metabolized by cytochrome P450 enzymes to highly reactive diol-epoxide metabolites that readily react with DNA or by phase II conjugation facilitating excretion. To complement prior in vitro metabolism studies with parent B[a]P and DBC, both phase I metabolism and phase II glucuronidation of B[a]P diol and DBC diol were measured in hepatic microsomes from female B6129SF1/J mice, male Sprague-Dawley rats, and female humans. Metabolic parameters, including intrinsic clearance and Michaelis-Menten kinetics were calculated from substrate depletion data. Mice and rats demonstrated similar B[a]P diol phase I metabolic rates. Compared to rodents, human phase I metabolism of B[a]P diol demonstrated lower overall metabolic capacity, lower intrinsic clearance at higher substrate concentrations (>0.14 µM), and higher intrinsic clearance at lower substrate concentrations (<0.07 µM). Rates of DBC diol metabolism did not saturate in mice or humans and were highest overall in mice. Higher affinity constants and lower capacities were observed for DBC diol glucuronidation compared to B[a]P diol glucuronidation; however, intrinsic clearance values for these compounds were consistent within each species. Kinetic parameters reported here will be used to extend physiologically based pharmacokinetic (PBPK) models to include the disposition of B[a]P and DBC metabolites in animal models and humans to support future human health risk assessments.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Sex-specific respiratory and systemic endocrine effects of acute acrolein and trichloroethylene inhalation

Acrolein and trichloroethylene (TCE) are priority hazardous air pollutants due to environmental prevalence and adverse health effects; however, neuroendocrine stress-related systemic effects are not characterized. Comparing acrolein, an airway irritant, and TCE with low irritancy, we hypothesized that airway injury would be linked to neuroendocrine-mediated systemic alterations. Male and female Wistar-Kyoto rats were exposed nose-only to air, acrolein or TCE in incremental concentrations over 30 min, followed by 3.5-hr exposure to the highest concentration (acrolein - 0.0, 0.1, 0.316, 1, 3.16 ppm; TCE - 0.0, 3.16, 10, 31.6, 100 ppm). Real-time head-out plethysmography revealed acrolein decreased minute volume and increased inspiratory-time (males>females), while TCE reduced tidal-volume. Acrolein, but not TCE, inhalation increased nasal-lavage-fluid protein, lactate-dehydrogenase activity, and inflammatory cell influx (males>females). Neither acrolein nor TCE increased bronchoalveolar-lavage-fluid injury markers, although macrophages and neutrophils increased in acrolein-exposed males and females. Systemic neuroendocrine stress response assessment indicated acrolein, but not TCE, increased circulating adrenocorticotrophic hormone, and consequently corticosterone, and caused lymphopenia, but only in males. Acrolein also reduced circulating thyroid-stimulating hormone, prolactin, and testosterone in males. Furthermore, acute acrolein inhalation resulted in sex-specific upper respiratory irritation/inflammation and systemic neuroendocrine alterations linked to hypothalamic-pituitary-adrenal axes activation, which is critical in mediating extra-respiratory effects.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Oocyte-specific deletion of Gsα induces oxidative stress and deteriorates oocyte quality in mice

Highlights: • Oocyte-specific disruption of G{sub s}α leads to female infertility in mice. • Deletion of G{sub s}α in oocytes causes poor oocyte quality and impaired early embryo development. • G{sub s}α deficiency in oocytes leads to oxidative stress. The stimulatory heterotrimeric G{sub s} protein alpha subunit (G{sub s}α) is a ubiquitous guanine nucleotide-binding protein that regulates the intracellular cAMP signaling pathway and consequently participates in a wide range of biological events. In the reproductive system, despite G{sub s}α being associated with oocyte meiotic arrest in vitro, the exact role of G{sub s}α in female fertility in vivo remains largely unknown. Here, we generated oocyte-specific G{sub s}α knockout mice by using the Cre/LoxP system. We observed that the deletion of G{sub s}α caused complete female infertility. Exclusion of post-implantation abnormalities, oogenesis, fertilization, and early embryo development was subsequently monitored; meiosis in G{sub s}α-deficient oocytes precociously resumed in only 43% of antral follicles from mutant mice, indicating that alteration of meiotic pause was not the key factor in infertility. Ovulation process and number were normal, but the rate of morphological abnormal oocytes was apparently increased; spindle organization, fertilization, and early embryo development were impaired. Furthermore, the level of ROS (reactive oxygen species) and the mitochondrial aggregation increased, and antioxidant glutathione (GSH) content, ATP level, mtDNA copy number, and mitochondrial membrane potential decreased in G{sub s}α-deficient oocytes. GV oocytes from mutant mice showed early-stage apoptosis. Meanwhile, the G{sub s}α knockout-induced decline in oocyte quality and low developmental potential was partially rescued by antioxidant supplementation. To sum up, our results are the first to reveal that the profile of G{sub s}α oocyte-specific deletion caused female infertility in vivo, and oxidative stress plays an important role in this event.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

A potent and selective C-11 labeled PET tracer for imaging sphingosine-1-phosphate receptor 2 in the CNS demonstrates sexually dimorphic expression

Sphingosine-1-phosphate receptor 2 (S1PR2) plays an essential role in regulating blood–brain barrier (BBB) function during demyelinating central nervous system (CNS) disease. Increased expression of S1PR2 occurs in disease-susceptible CNS regions of female versus male SJL mice and in female multiple sclerosis (MS) patients. Here we reported a novel sensitive and noninvasive method to quantitatively assess S1PR2 expression using a C-11 labeled positron emission tomography (PET) radioligand [ 11 C]5a for in vivo imaging of S1PR2. Compound 5a exhibited promising binding potency with IC 50 value of 9.52 ± 0.70 nM for S1PR2 and high selectivity over S1PR1 and S1PR3 (both IC 50 > 1000 nM). [ 11 C]5a was synthesized in ~40 min with radiochemistry yield of 20 ± 5% (decayed to the end of bombardment (EOB), n > 10), specific activity of 222–370 GBq μmol –1 (decayed to EOB). The biodistribution study in female SJL mice showed the cerebellar uptake of radioactivity at 30 min of post-injection of [11C]5a was increased by Cyclosporin A (CsA) pretreatment (from 0.84 ± 0.04 ID% per g to 2.21 ± 0.21 ID% per g, n = 4, p < 0.01). MicroPET data revealed that naive female SJL mice exhibited higher cerebellar uptake compared with males following CsA pretreatment (standardized uptake values (SUV) 0.58 ± 0.16 vs. 0.48 ± 0.12 at 30 min of post-injection, n = 4, p < 0.05), which was consistent with the autoradiographic results. This data suggested that [ 11 C]5a had the capability in assessing the sexual dimorphism of S1PR2 expression in the cerebellum of the SJL mice. Furthermore, the development of radioligands for S1PR2 to identify a clinical suitable S1PR2 PET radiotracer, may greatly contribute to investigating sex differences in S1PR2 expression that contribute to MS subtype and disease progression and it will be very useful for detecting MS in early state and differentiating MS with other patients with neuroinflammatory diseases, and monitoring the efficacy of treating diseases using S1PR2 antagonism.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2020

Kv2.1 channels play opposing roles in regulating membrane potential, Ca 2+ channel function, and myogenic tone in arterial smooth muscle

The accepted role of the protein Kv2.1 in arterial smooth muscle cells is to form K + channels in the sarcolemma. Opening of Kv2.1 channels causes membrane hyperpolarization, which decreases the activity of L-type Ca V 1.2 channels, lowering intracellular Ca 2+ ([Ca 2+ ] i ) and causing smooth muscle relaxation. A limitation of this model is that it is based exclusively on data from male arterial myocytes. Here, we used a combination of electrophysiology as well as imaging approaches to investigate the role of Kv2.1 channels in male and female arterial myocytes. We confirmed that Kv2.1 plays a canonical conductive role but found it also has a structural role in arterial myocytes to enhance clustering of Ca V 1.2 channels. Less than 1% of Kv2.1 channels are conductive and induce membrane hyperpolarization. Paradoxically, by enhancing the structural clustering and probability of Ca V 1.2–Ca V 1.2 interactions within these clusters, Kv2.1 increases Ca 2+ influx. These functional impacts of Kv2.1 depend on its level of expression, which varies with sex. In female myocytes, where expression of Kv2.1 protein is higher than in male myocytes, Kv2.1 has conductive and structural roles. Female myocytes have larger Ca V 1.2 clusters, larger [Ca 2+ ] i , and larger myogenic tone than male myocytes. In contrast, in male myocytes, Kv2.1 channels regulate membrane potential but not Ca V 1.2 channel clustering. We propose a model in which Kv2.1 function varies with sex: in males, Kv2.1 channels control membrane potential but, in female myocytes, Kv2.1 plays dual electrical and Ca V 1.2 clustering roles. This contributes to sex-specific regulation of excitability, [Ca 2+ ] i , and myogenic tone in arterial myocytes.

59 BASIC BIOLOGICAL SCIENCES↗