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At least 343 records · Page 19
All sourcesNASA NTRSDOE OSTI
DOE OSTI2018

The Interventional Radiology (IR) Gender Gap: A Prospective Online Survey by the Cardiovascular and Interventional Radiological Society of Europe (CIRSE)

AimA prospective online survey was conducted by the Cardiovascular Interventional Radiological Society of Europe (CIRSE) to evaluate the gender gap within interventional radiology (IR) and the barriers facing women in IR.Materials and MethodsA questionnaire (“Appendix”) was devised by the authors and the CIRSE communication and publication team and sent electronically to 750 identifiable female members of CIRSE. Responses were collected from 7 August to 24 August 2017.ResultsThe response rate was 19.9% (n = 149) with highest responses from UK (18%), Italy (11%), Germany (11%), Spain (7%), Netherlands (5%), France (5%), Sweden (4%), USA (4%). 91% of the respondents were between 31 and 46 years, 83% work full time, 62% spend > 50% of their working time in IR, and 67% practice in a university or tertiary referral institution. 85% were in the minority in their department. 52% had no leadership role in their department, but 67% expressed willingness to consider a leadership position. Their main concerns were work/family life balance, the risks of radiation exposure, the effect of pregnancy on training and practice and the male-dominated work environment.ConclusionThis survey highlights issues experienced by women in IR. Clear guidance on concerns regarding radiation exposure particularly during pregnancy is needed. Structured and supportive training is required for female IRs who may wish to train or work flexibly. The male-dominated environment is discouraging, and a scheme to promote female IRs would encourage women to take on senior leadership positions and attract more women into the specialty.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2016

Hybridization of downregulated-COMT transgenic switchgrass lines with field-selected switchgrass for improved biomass traits

Transgenic switchgrass (Panicum virgatum L.) has been produced for improved cell walls for biofuels. For instance, downregulated caffeic acid 3-O-methyltransferase (COMT) switchgrass produced significantly more biomass and biofuel than the non-transgenic progenitor line. In this present study we sought to further improve biomass characteristics by crossing the downregulated COMT T 1 lines with high-yielding switchgrass accessions in two genetic backgrounds ('Alamo' and 'Kanlow'). Crosses and T 2 progeny analyses were made under greenhouse conditions to assess maternal effects, plant morphology and yield, and cell wall traits. Female parent type influenced morphology, but had no effect on cell wall traits. T 2 hybrids produced with T 1 COMT-downregulated switchgrass as the female parent were taller, produced more tillers, and produced 63% more biomass compared with those produced using the field selected accession as the female parent. Transgene status (presence or absence of transgene) influenced both growth and cell wall traits. T 2 transgenic hybrids were 7% shorter 80 days after sowing and produced 43% less biomass than non-transgenic null-segregant hybrids. Cell wall-related differences included lower lignin content, reduced syringyl-to-guaiacyl (S/G) lignin monomer ratio, and a 12% increase in total sugar release in the T 2 transgenic hybrids compared to non-transgenic null segregants. This is the first study to evaluate the feasibility of transferring the low-recalcitrance traits associated with a transgenic switchgrass line into high-yielding field varieties in an attempt to improve growth-related traits. Lastly, our results provide insights into the possible improvement of switchgrass productivity via biotechnology paired with plant breeding.

09 BIOMASS FUELS↗
DOE OSTI2023

Home range and resource selection of Virginia opossums in the rural southeastern United States

The Virginia opossum (Didelphis virginiana) has a rapidly expanding distribution in North America, but many aspects of its ecology remain relatively understudied, particularly in rural areas of its core range. We collected GPS telemetry data from 93 opossums in a rural, non-agricultural landscape in South Carolina, USA (2018–2019) to examine factors influencing space use and resource selection. Estimated male home ranges (99% utilization distributions) were on average 50% larger than those of females (mean home range 115.9 ± 103.7 ha vs 76.7 ± 75.0 ha). The home range size decreased on average by 20% with each 20% increase in deciduous land cover but was not affected by season or other landscape factors. Core area sizes (65% utilization distributions) were not influenced by sex (mean core area size 29.1 ± 23.7 ha and 22.4 ha ± 13.8 for males and females, respectively) or season, but the core area size decreased by 14% with each 400 m increase in distance from a permanent water source. Resource selection by opossums primarily occurred at the landscape level. Both males and females generally selected for wetlands while avoiding pine forests and developed/open areas, likely the result of differences in resource availability and predation risk between habitats. Opossums also tended to select for linear features such as unpaved roads and edge habitat, which may facilitate movement across the landscape. Finally, the home ranges we documented are among the largest recorded for opossums in the USA, likely the result of the relatively low resource abundance throughout our study area due to comparatively minimal anthropogenic influence.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2014

Apolipoprotein E-knockout mice on high-fat diet show autoimmune injury on kidney and aorta

Highlights: • Titers of ANA and anti-dsDNA antibodies were similar in ApoE{sup −/−} and Fas{sup −/−} mice. • The spleen weights and glomerular areas were similar in ApoE{sup −/−} and Fas{sup −/−} mice. • Expressions of IgG and C3 in glomeruli were similar in ApoE{sup −/−} and Fas{sup −/−} mice. • IgG, C3 and macrophage infiltration in aortic plaques were found in ApoE{sup −/−} mice. - Abstract: Background: Apolipoprotein E-knockout (ApoE{sup −/−}) mice is a classic model of atherosclerosis. We have found that ApoE{sup −/−} mice showed splenomegaly, higher titers of serum anti-nuclear antibody (ANA) and anti-dsDNA antibody compared with C57B6/L (B6) mice. However, whether ApoE{sup −/−} mice show autoimmune injury remains unclear. Methods and results: Six females and six males in each group, ApoE{sup −/−}, Fas{sup −/−} and B6 mice, were used in this study. The titers of serum ANA, anti-dsDNA antibody and creatinine and urine protein were measured by ELISA after 4 months of high-fat diet. The spleen weight and the glomerular area were determined. The expressions of IgG, C3 and macrophage in kidney and atherosclerotic plaque were detected by immunostaining followed by morphometric analysis. Similar to the characteristics of Fas{sup −/−} mice, a model of systemic lupus erythematosus (SLE), ApoE{sup −/−} mice, especially female, displayed significant increases of spleen weight and glomerular area when compared to B6 mice. Also, elevated titers of serum ANA, anti-dsDNA antibody and creatinine and urine protein. Moreover, the expressions of IgG, C3 and macrophage in glomeruli and aortic plaques were found in ApoE{sup −/−} mice. In addition, the IgG and C3 expressions in glomeruli and plaques significantly increased (or a trend of increase) in female ApoE{sup −/−} mice compared with males. Conclusions: Apolipoprotein E-knockout mice on high-fat diet show autoimmune injury on kidney and aorta.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Lixisenatide reduces amyloid plaques, neurofibrillary tangles and neuroinflammation in an APP/PS1/tau mouse model of Alzheimer's disease

Highlights: • Lixisenatide reduced amyloid plaques, neurofibrillary tangles and neuroinflammation. • Activiation of PKA-CREB and inhibition of p38-MAPK were the protective mechanisms. • Lixisenatide might have the potential to be developed as a novel therapy for AD. Type 2 diabetes mellitus (T2DM) has been identified as a high risk factor for Alzheimer's disease (AD). The impairment of insulin signaling has been found in AD brain. Glucagon-like peptide-1 (GLP-1) is an incretin hormone, normalises insulin signaling and acts as a neuroprotective growth factor. We have previously shown that the long-lasting GLP-1 receptor (GLP-1R) agonist lixisenatide plays an important role in memory formation, synaptic plasticity and cell proliferation of rats. In the follow-up study, we analysed the neuroprotective effect and mechanism of lixisenatide, injected for 60 days at 10 nmol/kg i.p. once daily in APP/PS1/tau female mice and C57BL/6J female mice (as control) aged 12 month. The results showed that lixisenatide could reduce amyloid plaques, neurofibrillary tangles and neuroinflammation in the hippocampi of 12-month-old APP/PS1/tau female mice; activation of PKA-CREB signaling pathway and inhibition of p38-MAPK might be the important mechanisms in the neuroprotective function of lixisenatide. The study demonstrated that GLP-1R agonists such as lixisenatide might have the potential to be developed as a novel therapy for AD.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Identification and characterization of the zinc finger protein SjZF in Schistosoma japonicum

Highlights: • The zinc finger protein SjZF in S. japonicum was identified and characterized. • SjZF was mainly located in the intestinal tract of adult worms and the vitelline glands of females. • The rSjZF induced significant protection against S. japonicum infection in mouse. Schistosomiasis represents one of the most prevalent parasitic infections affecting over 249 million people worldwide. The pathological damage is mainly caused by the eggs laid by female schistosomes. Zinc finger proteins (ZFPs) usually play critical roles in many biological functions. In this study, we cloned, identified and characterized the zinc finger protein SjZF of Schistosoma japonicum. SjZF ortholog proteins were also identified in S. mansoni, S. haematobium, Opisthorchis viverrini and O. sinensis. Fluorescence localization showed that SjZF was particularly expressed in the worm gut of both genders and the vitelline glands of females. In vitro RNAi assay indicated that decreased expression of SjZF could affect the survival rate of adult worms. The immune protection assay indicated that rSjZF did partially protect mice with 54.8% reduction in the worm burden and 34.1% reduction in the liver eggs. Taken in concert, our preliminary results suggest that SjZF may be a potential vaccine candidate for schistosomiasis and may further provide evidence for a possible role of SjZF in the development of schistosomes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Conversion of dietary trans-vaccenic acid to trans11,cis13-conjugated linoleic acid in the rat lactating mammary gland by Fatty Acid Desaturase 3-catalyzed methyl-end Δ13-desaturation

Highlights: • FADS3 was shown in vitro to catalyze the Δ13-desaturation of trans-vaccenic acid. • The product is the trans11,cis13-18:2 conjugated linoleic acid isomer. • The proof of this concept is so far lacking in vivo. • Lactating female rats fed with trans-vaccenic acid produced the trans11,cis13-18:2. • This study demonstrates this new pathway in the lactating mammary gland. In vitro, the rat Fatty Acid Desaturase 3 (FADS3) gene was shown to code for an enzyme able to catalyze the unexpected Δ13-desaturation of trans-vaccenic acid, producing the trans11,cis13-conjugated linoleic acid (CLA) isomer. FADS3 may therefore be the first methyl-end trans-vaccenate Δ13-desaturase functionally characterized in mammals, but the proof of this concept is so far lacking in vivo. The present study therefore aimed at investigating further the putative in vivo synthesis of trans11,cis13-CLA from dietary trans-vaccenic acid in rodents. During one week of pregnancy and two weeks post-partum, Sprague-Dawley female rats were fed two diets either high (10.0% of fatty acids and 3.8% of energy intake) or low (0.4% of fatty acids and 0.2% of energy intake) in trans-vaccenic acid. The trans11,cis13-CLA was specifically detected, formally identified and reproducibly quantified (0.06% of total fatty acids) in the mammary gland phospholipids of lactating female rats fed the high trans-vaccenic acid-enriched diet. This result was consistent with FADS3 mRNA expression being significantly higher in the lactating mammary gland than in the liver. Although the apparent metabolic conversion is low, this physiological evidence demonstrates the existence of this new pathway described in the lactating mammary gland and establishes the FADS3 enzyme as a reliable mammalian trans-vaccenate Δ13-desaturase in vivo.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Perfluoroalkyl substances in diamondback terrapins (Malaclemys terrapin) in coastal South Carolina

This paper focused on an estuarine wildlife species exhibiting high site fidelity and ubiquitous distribution in coastal environments along the Atlantic and Gulf coasts of the United States to monitor per- and polyfluoroalkyl substances (PFAS). A total of 75 diamondback terrapin (Malaclemys terrapin) plasma samples were collected from five creeks associated with Kiawah (Oyster Creek, Fiddler Creek, Sandy Creek, Gnat Creek) and Edisto (Townsend Creek) islands in Charleston County, South Carolina and investigated for 15 legacy PFAS. Of those, PFHxS was the only PFAS found in all terrapin plasma samples. Four additional PFAS were routinely detected (greater than 90% of the samples) and were included in statistical analyses: PFOS, PFNA, PFDA, and PFUnA. Sex-differences were observed for two creeks with male plasma containing higher PFAS than female plasma (PFHxS at Townsend Creek, PFOS at Oyster Creek). Sex-specific site differences in PFAS concentrations were observed primarily for males, suggesting male terrapins may be more sensitive indicators of localized contaminant profiles than females. Three PFAS were observed to have negative correlations with body mass: PFOS in males (p = 0.045, tau = -0.220), PFNA in males (p = 0.016, tau = -0.269), and PFHxS in both males (p = 0.007, tau = -0.302) and females (p = 0.001, tau = -0.379). Finally, no relationships for body mass and PFDA and PFUnA were observed.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2016

High feather mercury concentrations in the wandering albatross are related to sex, breeding status and trophic ecology with no demographic consequences

Hg can affect physiology of seabirds and ultimately their demography, particularly if they are top consumers. In the present study, body feathers of >200 wandering albatrosses from Possession Island in the Crozet archipelago were used to explore the potential demographic effects of the long-term exposure to Hg on an apex predator. Variations of Hg with sex, age class, foraging habitat (inferred from δ{sup 13}C values), and feeding habits (inferred from δ{sup 15}N values) were examined as well as the influence of Hg on current breeding output, long-term fecundity and survival. Wandering albatrosses displayed among the highest Hg feather concentrations reported for seabirds, ranging from 5.9 to 95 µg g{sup −1}, as a consequence of their high trophic position (δ{sup 15}N values). These concentrations fall within the same range of those of other wandering albatross populations from subantarctic sites, suggesting that this species has similar exposure to Hg all around the Southern Ocean. In both immature and adult albatrosses, females had higher Hg concentrations than males (28 vs. 20 µg g{sup −1} dw on average, respectively), probably as a consequence of females foraging at lower latitudes than males (δ{sup 13}C values). Hg concentrations were higher in immature than in adult birds, and they remained fairly constant across a wide range of ages in adults. Such high levels in immature individuals question (i) the frequency of moult in young birds, (ii) the efficiency of Hg detoxification processes in immatures compared to adults, and (iii) importantly the potential detrimental effects of Hg in early life. Despite very high Hg concentrations in their feathers, neither effects on adults' breeding probability, hatching failure and fledgling failure, nor on adults' survival rate were detected, suggesting that long-term bioaccumulated Hg was not under a chemical form leading to deleterious effects on reproductive parameters in adult individuals. - Highlights: • Immature albatrosses had higher feather Hg concentrations than adults. • Foraging habitat influenced Hg bioaccumulation as a result of male and female segregation. • No carry-over effects were detected on reproductive parameters.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Maternal and paternal serum concentrations of persistent organic pollutants and the secondary sex ratio: A population-based preconception cohort study

Highlights: • Recent declines in the SSR in some countries may be attributed to exposure to POPs. • Maternal PCB 128 and paternal HCB were associated with a female excess. • Maternal mirex and paternal PCB 128 and p,p′-DDE were associated with a male excess. • These findings await corroboration given the exploratory design of this study. Recent declines in the secondary sex ratio (SSR), defined as the ratio of males to females at birth, in some industrialized countries may be attributed to exposure to environmental toxicants such as persistent organic pollutants (POPs). This study aimed to evaluate the association of couples’ preconception exposure to POPs with the SSR. The study cohort comprised 235 couples who were enrolled in the Longitudinal Investigation of Fertility and the Environment (LIFE) Study between 2005 and 2009 prior to conception and prospectively followed through delivery of a singleton birth. Upon enrollment, couples’ serum concentrations (ng/g) were measured for 9 organochlorine pesticides, 1 polybrominated biphenyl, 10 polybrominated diphenyl ethers, and 36 polychlorinated biphenyls (PCBs). Birth outcome data including infant sex were collected upon delivery. Modified Poisson regression models were used to estimate the relative risks (RRs) and 95% confidence intervals (CIs) of a male birth for each chemical. Of the 56 POPs examined, maternal PCB 128 and paternal hexachlorobenzene were significantly associated with a female excess (RRs, 0.75 [95% CI, 0.60–0.94] and 0.81 [95% CI, 0.68–0.97] per 1 SD increase in log-transformed serum chemical concentrations, respectively), whereas maternal mirex and paternal PCB 128 and p,p′-dichlorodiphenyldichloroethylene were significantly associated with a male excess (RR range, 1.10–1.22 per 1 SD increase in log-transformed serum chemical concentrations). After adjusting for multiple comparisons, only maternal mirex remained significantly associated with the SSR. This exploratory study on multiple classes of POPs demonstrated no conclusive evidence on the association between parental preconception exposure to POPs and the SSR.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Persistent organic pollutants, skull size and bone density of polar bears (Ursus maritimus) from East Greenland 1892–2015 and Svalbard 1964–2004

Highlights: • Density in East Greenland males decreased over time. • Size in East Greenland females tented to decrease over time. • Size was highest in Svalbard polar bears. • Density was positive correlated to POPs. • Environmental changes and POPs may affect bone density and size. We investigated skull size (condylobasal length; CBL) and bone mineral density (BMD) in polar bears (Ursus maritimus) from East Greenland (n = 307) and Svalbard (n = 173) sampled during the period 1892–2015 in East Greenland and 1964–2004 at Svalbard. Adult males from East Greenland showed a continuous decrease in BMD from 1892 to 2015 (linear regression: p < 0.01) indicating that adult male skulls collected in the early pre-pollution period had the highest BMD. A similar decrease in BMD over time was not found for the East Greenland adult females. However, there was a non-significant trend that the skull size of adult East Greenland females was negatively correlated with collection year 1892–2015 (linear regression: p = 0.06). No temporal change was found for BMD or skull size in Svalbard polar bears (ANOVA: all p > 0.05) nor was there any significant difference in BMD between Svalbard and East Greenland subpopulations. Skull size was larger in polar bears from Svalbard than from East Greenland (two-way ANOVA: p = 0.003). T-scores reflecting risk of osteoporosis showed that adult males from both East Greenland and Svalbard are at risk of developing osteopenia. Finally, when correcting for age and sex, BMD in East Greenland polar bears increased with increasing concentrations of persistent organic pollutants (POPs) i.e. ΣPCB (polychlorinated biphenyls), ΣHCH (hexachlorohexane), HCB (hexachlorobenzene) and ΣPBDE (polybrominated diphenyl ethers) while skull size increased with ΣHCH concentrations all in the period 1999–2014 (multiple linear regression: all p < 0.05, n = 175). The results suggest that environmental changes over time, including exposure to POPs, may affect bone density and size of polar bears.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Persistent organic pollutants as predictors of increased FSH:LH ratio in naturally cycling, reproductive age women

Highlights: • Endocrine disrupting chemicals pose a threat to female fecundity and reproduction. • Examined organochlorines and a marker of ovarian responsivity, FSH:LH ratio. • Increasing concentrations of estrogenic PCBs predict FSH:LH ratio > 2. • PCB congeners related to airborne exposure are associated with FSH:LH ratio > 2. Although several recent studies suggest endocrine disrupting compounds, such as polychlorinated biphenyls (PCBs), dichlorodiphenyldichloroethylene (p,p′, DDE), and hexachlorobenzene (HCB), target different organs and systems in the body, their impact on female reproductive function in humans is not well characterized. We seek to determine the relationship between several known endocrine disrupting compounds and a marker of ovarian responsivity, the FSH:LH ratio (higher ratio indicates less ovarian responsivity). For this analysis, 169 naturally cycling women between 21 and 38 years of age completed interviews and had their blood drawn on day 3 of their menstrual cycle for analyses of toxicants, gonadal sex hormones (E{sub 2} and P{sub 4}), and gonadotropins (FSH and LH). PCB congeners were classified into five groups based on their environmental persistence, distribution in human tissue, and toxicological action, reflecting the structure, mechanism, and known biological activity of individual PCB congeners. For every unit (ppb) increase in the level of the estrogenic PCB group, there was a 5-fold greater risk of a FSH:LH ratio ≥ 2, controlling for individual differences in age, percent body fat, cycle day 3 estradiol levels, parity, alcohol use and cigarette smoking in the past year (exp[ß] = 5; p = ≤0.01). PCB congeners identified as estrogenic were analyzed individually, and, of the 19 potentially estrogenic congeners, five were significantly, and positively related to an increased FSH:LH ratio. Four of these congeners are non-persistent, easily volatilize in the environment, and are easily metabolized, and hence, are indicative of very recent or current exposure. p,p′-DDE and HCB were not associated with FSH:LH ratio. We find a clinical indicator of ovarian responsivity, FSH:LH ratio, is associated with a specific group of estrogenic PCBs. These congeners may become airborne when they volatilize from dredged PCB-contaminated soil or from indoor PCB-containing window caulk and sealants in older buildings leading to inhalation exposure. PCB exposure, particularly to non-persistent, estrogenic congeners, may pose an unrecognized threat to female fecundity within the general population.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2023

Relationships between maternally-transferred mercury and hatchling development, behavior, and survival in the American alligator ( Alligator mississippiensis )

Mercury is a toxic and pervasive environmental contaminant that can be transferred from mother to offspring during development. Consequences of maternally-transferred mercury have been observed in vertebrate taxa, including reduced clutch viability, reduced offspring size, and behavioral alterations. These sublethal effects have been assumed to decrease survivorship, though this is seldom assessed. Here, we examined how maternally-transferred mercury interacts with incubation temperature to influence reproductive success, offspring behavior, and subsequent survival in the American alligator (Alligator mississippiensis). We collected nine clutches of eggs from a mercury contaminated reservoir on the Savannah River Site, South Carolina, and incubated eggs at either female- or male-promoting temperatures. Clutch-averaged mercury in egg yolk was high relative to other studies in crocodilians and ranged from 0.248 to 0.554 ppm compared to 0.018–0.052 ppm at a site with low levels of mercury contamination; mercury levels in hatchling blood ranged from 0.090 to 0.490 ppm ($\overline{x}$= 0.240 ppm, n = 158). We found few, mostly negligible correlations between life history traits and mercury but noted a positive relationship with egg mass, possibly mediated by correlated maternal effects such as resource provisioning. Incubation temperature exerted strong effects on hatchling phenotypes, with warmer, male-promoting temperatures producing larger and bolder hatchlings. Presumptive females, produced from cooler incubation temperatures, spent more time in warm areas during behavior trials. Hatchlings were released 10–15 days post-hatch and surveyed over eight months to assess survival. Survivorship was positively correlated with hatchling size and negatively correlated with proportional time spent in warm areas. Presumptive females had much lower survival, and overall survivorship for the eight-month period was 0.185–0.208, depending on the modelling approach. Finally, our study suggests that, within the range of concentrations we observed, incubation temperature has a stronger effect on offspring behavior and survival than maternally-transferred mercury pollution in American alligators.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2014

Transcriptional responses in the rat nasal epithelium following subchronic inhalation of naphthalene vapor

Male and female Fischer 344 rats were exposed to naphthalene vapors at 0 (controls), 0.1, 1, 10, and 30 ppm for 6 h/d, 5 d/wk, over a 90-day period. Following exposure, the respiratory epithelium and olfactory epithelium from the nasal cavity were dissected separately, RNA was isolated, and gene expression microarray analysis was conducted. Only a few significant gene expression changes were observed in the olfactory or respiratory epithelium of either gender at the lowest concentration (0.1 ppm). At the 1.0 ppm concentration there was limited evidence of an oxidative stress response in the respiratory epithelium, but not in the olfactory epithelium. In contrast, a large number of significantly enriched cellular pathway responses were observed in both tissues at the two highest concentrations (10 and 30 ppm, which correspond to tumorigenic concentrations in the NTP bioassay). The nature of these responses supports a mode of action involving oxidative stress, inflammation and proliferation. These results are consistent with a dose-dependent transition in the mode of action for naphthalene toxicity/carcinogenicity between 1.0 and 10 ppm in the rat. In the female olfactory epithelium (the gender/site with the highest incidences of neuroblastomas in the NTP bioassay), the lowest concentration at which any signaling pathway was significantly affected, as characterized by the median pathway benchmark dose (BMD) or its 95% lower bound (BMDL) was 6.0 or 3.7 ppm, respectively, while the lowest female olfactory BMD values for pathways related to glutathione homeostasis, inflammation, and proliferation were 16.1, 11.1, and 8.4 ppm, respectively. In the male respiratory epithelium (the gender/site with the highest incidences of adenomas in the NTP bioassay), the lowest pathway BMD and BMDL were 0.4 and 0.3 ppm, respectively, and the lowest male respiratory BMD values for pathways related to glutathione homeostasis, inflammation, and proliferation were 0.5, 0.7, and 0.9 ppm, respectively. Using a published physiologically based pharmacokinetic (PBPK) model to estimate target tissue dose relevant to the proposed mode of action (total naphthalene metabolism per gram nasal tissue), the lowest transcriptional BMDLs from this analysis equate to human continuous naphthalene exposure at approximately 0.3 ppm. It is unlikely that significant effects of naphthalene or its metabolites will occur at exposures below this concentration. - Highlights: • We investigated mode of action for carcinogenicity of inhaled naphthalene in rats. • Gene expression changes were measured in rat nasal tissues after 90 day exposures. • Support a non-linear mode of action (oxidative stress, inflammation, and proliferation) • Suggest a dose-dependent transition in the mode of action between 1.0 and 10 ppm • Transcriptional benchmark doses could inform point of departure for risk assessment.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Methyl parathion inhibits the nuclear maturation, decreases the cytoplasmic quality in oocytes and alters the developmental potential of embryos of Swiss albino mice

Methyl parathion (MP) is one of the most commonly used and extremely toxic organophosphorous group of pesticide. A large number of studies in the literature suggest that it has adverse effects on the male reproductive system. However, there is limited information about its toxicity to the female reproductive system. In the present study we report the toxic effects of methyl parathion on the female reproductive system using Swiss albino mice as the experimental model. The female mice were administered orally with 5, 10 and 20 mg/kg of MP. One week later, the mice were superovulated with pregnant mare serum gonadotrophin (PMSG) and human chorionic gonadotrophin (hCG) to study the quality of the oocytes, spindle organization, developmental potential of early embryos and the DNA integrity in blastocysts. MP exposure resulted in a non-significant decrease in the number of primordial follicles and increased DNA damage in granulosa cells. Though MP did not have any effect on the ovulation it had a significant inhibitory effect on the nuclear maturity of oocytes which was associated with spindle deformity. In addition, the oocytes had higher cytoplasmic abnormalities with depleted glutathione level. Even though it did not have any effect on the fertilization and blastocyst rate at lower doses, at 20 mg/kg MP it resulted in a significant decrease in blastocyst hatching, decrease in cell number and high DNA damage. While low body weight gain was observed in F1 generation from 5 mg/kg group, at higher dose, the body weight in F1 generation was marginally higher than control. Post-natal death in F1 generation was observed only in mice treated with 20 mg/kg MP. In conclusion, we report that MP has adverse effects on the oocyte quality, developmental potential of the embryo and reproductive outcome. - Highlights: • Methyl parathion induces severe cytoplasmic abnormalities in oocytes. • Inhibits nuclear maturation and spindle damage • Poor blastocyst quality and high DNA damage.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Application of physiologically-based pharmacokinetic modeling to explore the role of kidney transporters in renal reabsorption of perfluorooctanoic acid in the rat

ABSTRACT: Renal elimination and the resulting clearance of perfluorooctanoic acid (PFOA) from the serum exhibit pronounced sex differences in the adult rat. The literature suggests that this is largely due to hormonally regulated expression of organic anion transporters (OATs) on the apical and basolateral membranes of the proximal tubule cells that facilitate excretion and reabsorption of PFOA from the filtrate into the blood. Previously developed PBPK models of PFOA exposure in the rat have not been parameterized to specifically account for transporter-mediated renal elimination. We developed a PBPK model for PFOA in male and female rats to explore the role of Oat1, Oat3, and Oatp1a1 in sex-specific renal reabsorption and excretion of PFOA. Descriptions of the kinetic behavior of these transporters were extrapolated from in vitro studies and the model was used to simulate time-course serum, liver, and urine data for intravenous (IV) and oral exposures in both sexes. Model predicted concentrations of PFOA in the liver, serum, and urine showed good agreement with experimental data for both male and female rats indicating that in vitro derived physiological descriptions of transporter-mediated renal reabsorption can successfully predict sex-dependent excretion of PFOA in the rat. This study supports the hypothesis that sex-specific serum half-lives for PFOA are largely driven by expression of transporters in the kidney and contribute to the development of PBPK modeling as a tool for evaluating the role of transporters in renal clearance. - Highlights: • The PBPK model for PFOA in the rat explores the role of OATs in sex-specific clearance. • Descriptions of OAT kinetics were extrapolated from in vitro studies. • Model predictions showed good fit with experimental data for male and female rats.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Resveratrol protects the ovary against chromium-toxicity by enhancing endogenous antioxidant enzymes and inhibiting metabolic clearance of estradiol

Resveratrol (RVT), a polyphenolic component in grapes and red wine, has been known for its cytoprotective actions against several diseases. However, beneficial effects of RVT against early exposure to endocrine disrupting chemicals (EDCs) have not been understood. EDCs are linked to several ovarian diseases such as premature ovarian failure, polycystic ovary syndrome, early menopause and infertility in women. Hexavalent chromium (CrVI) is a heavy metal EDC, and widely used in > 50 industries. Environmental contamination with CrVI in the US is rapidly increasing, predisposing the human to several illnesses including cancers and still birth. Our lab has been involved in determining the molecular mechanism of CrVI-induced female infertility and intervention strategies to mitigate CrVI effects. Lactating mother rats were exposed to CrVI (50 ppm potassium dichromate) from postpartum days 1–21 through drinking water with or without RVT (10 mg/kg body wt., through oral gavage daily). During this time, F1 females received respective treatments through mother's milk. On postnatal day (PND) 25, blood and the ovary, kidney and liver were collected from the F1 females for analyses. CrVI increased atresia of follicles by increasing cytochrome C and cleaved caspase-3; decreasing antiapoptotic proteins; decreasing estradiol (E{sub 2}) biosynthesis and enhancing metabolic clearance of E{sub 2}, increasing oxidative stress and decreasing endogenous antioxidants. RVT mitigated the effects of CrVI by upregulating cell survival proteins and AOXs; and restored E{sub 2} levels by inhibiting hydroxylation, glucuronidation and sulphation of E{sub 2}. This is the first study to report the protective effects of RVT against any toxicant in the ovary. - Highlights: • Resveratrol (RVT) protects the ovary against CrVI-toxicity. • RVT mitigated CrVI-induced apoptosis and follicle atresia. • RVT restored estradiol level against CrVI-toxicity. • RVT inhibited metabolic clearance of estradiol in the ovary, kidney and liver. • RVT mitigated CrVI toxicity by upregulating cell survival proteins and antioxidants.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Sub-chronic 90-day toxicity of neamine in SD rats and its anti-liver cancer activity in vitro and in vivo

Neamine, an inhibitor of angiogenin (ANG), is a new investigative anticancer drug currently in preclinical stage. Here we report the 90-day sub-chronic toxicity of neamine in SD rats and its anti-liver cancer activity in vitro and in vivo. Neamine has a No Observed Adverse Effect Level (NOAEL) of 12 and 16 mg·kg{sup −1}·d{sup −1} for female and male rats, respectively. No mortality was found. The adverse effects included increased organ coefficients of spleen and kidney, increased BUN in both female and male rats at high dose, increased CR and decreased organ coefficients of heart and liver in male rats at high dose. All of which, except the kidney coefficient and BUN in males, returned to normal levels after 28-day recovery. Histopathological examination revealed vacuolar degeneration of glomerulus, degeneration of renal tubules and cast in the kidneys, which were also recovered except in males of high-dosing group. These results indicate that kidney is the most susceptible organ for neamine toxicity. Tissue microarray analysis validated that ANG is up-regulated in hepatocellular carcinoma accompanied by increased nuclear translocation, suggesting that ANG is a possible target for drug development in liver cancer treatment. Neamine blocked nuclear translocation of ANG in HUVEC and HepG2 cells, and inhibited ANG-stimulated cell proliferation without affecting basal level cell proliferation. Neamine also inhibited progression of HepG2 xenografts in athymic mice accompanied by decreased angiogenesis and cancer cell proliferation. These results suggest that neamine is a specific ANG inhibitor with low toxicity and high anti-liver cancer efficacy. - Highlights: • The NOAEL of neamine is 12 mg·kg{sup −1}·d{sup −1} for females and 16 mg·kg{sup −}1·d{sup −1} for males. • The most susceptible organ for neamine toxicity is kidney. • Neamine inhibits the progression of xenograft HepG2 liver cancer in athymic mice.

60 APPLIED LIFE SCIENCES↗