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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 415 records · Page 23
All sourcesNASA NTRSDOE OSTI
NASA NTRS1998

Regulation of the collagenase-3 receptor and its role in intracellular ligand processing in rat osteoblastic cells

We have previously described a specific, saturable receptor for rat collagenase-3 in the rat osteosarcoma cell line, UMR 106-01. Binding of rat collagenase-3 to this receptor is coupled to the internalization and eventual degradation of the enzyme and correlates with observed extracellular levels of the enzyme. In this study we have shown that decreased binding, internalization, and degradation of 125I-rat collagenase-3 were observed in cells after 24 h of parathyroid hormone treatment; these activities returned to control values after 48 h and were increased substantially (twice control levels) after 96 h of treatment with the hormone. Subcellular fractionation studies to identify the route of uptake and degradation of collagenase-3 localized intracellular accumulation of 125I-rat collagenase-3 initially in Golgi-associated lysosomes and later in secondary lysosomes. Maximal lysosomal accumulation of the radiolabel and stimulation of general lysosomal activity occurred after 72 h of parathyroid hormone treatment. Preventing fusion of endosomes with lysosomes (by temperature shift, colchicine, or monensin) resulted in no internalized 125I-collagenase-3 in either lysosomal fraction. Treatment of UMR cells with the above agents or ammonium chloride decreased excretion of 125I-labeled degradation products of collagenase-3. These experiments demonstrated that degradation of collagenase-3 required receptor-mediated endocytosis and sequential processing by endosomes and lysosomes. Thus, parathyroid hormone regulates the expression and synthesis of collagenase-3 as well as the abundance and functioning of the collagenase-3 receptor and the intracellular degradation of its ligand. The coordinate changes in the secretion of collagenase-3 and expression of the receptor determine the net abundance of the enzyme in the extracellular space.

NASA Discipline Musculoskeletal↗
NASA NTRS1996

Skeletal response to corticosteroid deficiency and excess in growing male rats

The study was designed to investigate bone histomorphometric changes induced by corticosteroid deficiency and supplementation at different dose levels in the rat skeleton. Male rats were adrenalectomized (ADX) or sham-operated and divided into six groups. At 2 days after surgery, sham-operated control rats (CON + PLA) and one group of ADX rats (ADX + PLA) were implanted subcutaneously (s.c.) with placebo pellets. ADX rats in the remaining four groups (ADX + C25, ADX + C50, ADX + C100, and ADX + C300) were implanted sc with corticosterone pellets designed to release 25, 50, 100, or 300 mg of the hormone over a 60 day period. Each ADX rat was also implanted sc with an aldosterone pellet (2.5 mg) similarly designed to release its contents over the same time period. All rats were killed at 3 weeks after implantation of pellets. Terminal blood samples were collected for serum biochemistry and the proximal tibial metaphyses (PTM), tibial diaphyses, and first lumbar vertebrae (LV) were processed undecalcified for quantitative bone histomorphometry. A dose-dependent increase in serum corticosterone concentration was observed in ADX rats implanted with hormone pellets. In comparison to CON + PLA rats, ADX + PLA rats had lower cancellous bone volume associated with a stimulation in longitudinal bone growth, an increase in mineral apposition rate, and a trend for increased osteoclast and osteoblast surfaces in PTM. In contrast, cancellous bone of ADX + C25 rats was preserved at nearly the CON + PLA level. However, the higher doses of corticosterone increased cancellous bone mass, but decreased longitudinal bone growth and all indices of bone resorption and formation in a dose-dependent manner in PTM. Similar cancellous bone changes were observed in the LV of corticosterone-treated rats, with the exception of a lack of an hormonal effect on cancellous bone mass. In the tibial diaphysis, corticosterone inhibited periosteal bone formation in a dose-dependent manner, but did not affect cortical bone mass. The results indicate that corticosteroid deficiency induces cancellous osteopenia, whereas supplementation with a near physiologic dose of the hormone prevents this bone loss in ADX rats. Furthermore, corticosteroid excess inhibits bone growth and bone turnover in a dose-dependent manner, but does not induce cancellous osteopenia in growing male rats.

Non-NASA Center↗
NASA NTRS2015

Menstrual Cycle Control in Female Astronauts and the Associated Risk of Venous Thromboembolism

Venous thromboembolism (VTE) is a common and serious condition affecting approximately 1‐2 per 1000 people in the USA every year. There have been no documented case reports of VTE in female astronauts during spaceflight in the published literature. Some female astronauts use hormonal contraception to control their menstrual cycles and it is currently unknown how this affects their risk of VTE. Current terrestrial risk prediction models do not account for the spaceflight environment and the physiological changes associated with it. We therefore aim to estimate a specific risk score for female astronauts who are taking hormonal contraception for menstrual cycle control, to deduce whether they are at an elevated risk of VTE. A systematic review of the literature was conducted in order to identify and quantify known terrestrial risk factors for VTE. Studies involving analogues for the female astronaut population were also reviewed, for example, military personnel who use the oral contraceptive pill for menstrual suppression. Well known terrestrial risk factors, for example, obesity or smoking would not be applicable to our study population as these candidates would have been excluded during astronaut selection processes. Other risk factors for VTE include hormonal therapy, lower limb paralysis, physical inactivity, hyperhomocysteinemia, low methylfolate levels and minor injuries, all of which potentially apply to crew members LSAH data will be assessed to identify which of these risk factors are applicable to our astronaut population. Using known terrestrial risk data, an overall estimated risk of VTE for female astronauts using menstrual cycle control methods will therefore be calculated. We predict this will be higher than the general population but not significantly higher requiring thromboprophylaxis. This study attempts to delineate what is assumed to be true of our astronaut population, for example, they are known to be a healthy fit cohort of individuals, and combine physiological impacts of spaceflight (cephalic fluid shifts, lower limb inactivity) to understand specific risks associated with hormonal contraception.

Jain, Varsha↗
DOE OSTI2016

High inorganic phosphate causes DNMT1 phosphorylation and subsequent fibrotic fibroblast activation

Phosphate is an essential constituent of critical cellular functions including energy metabolism, nucleic acid synthesis and phosphorylation-dependent cell signaling. Increased plasma phosphate levels are an independent risk factor for lowered life-expectancy as well as for heart and kidney failure. Nevertheless, direct cellular effects of elevated phosphate concentrations within the microenvironment are poorly understood and have been largely neglected in favor of phosphor-regulatory hormones. Because interstitial fibrosis is the common determinant of chronic progressive kidney disease, and because fibroblasts are major mediators of fibrogenesis, we here explored the effect of high extracellular phosphate levels on renal fibroblasts. We demonstrate that high inorganic phosphate directly induces fibrotic fibroblast activation associated with increased proliferative activity, increased expression of α-smooth muscle actin and increased synthesis of type I collagen. We further demonstrate that such fibroblast activation is dependent on phosphate influx, aberrant phosphorylation of DNA methyltransferase DNMT1 and aberrant CpG island promoter methylation. In summary, our studies demonstrate that elevated phosphate concentrations induce pro-fibrotic fibroblast activation independent of phospho-regulatory hormones. - Highlights: • We exposed human kidney fibroblasts to media containing 1 mM or 3 mM phosphate. • Increased phosphate influx causes phosphorylation of DNA methyltransferase Dnmt1. • Phosphorylated Dnmt1 causes promoter methylation and transcriptional silencing of RASAL1. • Depletion of RASAL1 causes increased intrinsic Ras-GTP activity and fibroblast activation. • Inorganic phosphate causes fibroblast activation independent of phospho-regulatory hormones.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Peripheral and central localization of the nesfatin-1 receptor using autoradiography in rats

Nesfatin-1 was recently identified and introduced as food intake-regulatory hormone. Soon thereafter, mounting evidence indicated a much broader role for nesfatin-1 with an involvement in the regulation of food intake, gastrointestinal motility, glucose homeostasis, blood pressure and stress. Despite the growing knowledge on the physiological regulation and functions of nesfatin-1, the receptor mediating these effects remains to be characterized. Therefore, the aim of this study was to investigate the peripheral and central localization of the nesfatin-1 receptor by autoradiography. Male Sprague–Dawley rats were used and peripheral as well as brain tissue was processed for {sup 125}I-nesfatin-1 autoradiography. In peripheral tissues, an autoradiographic signal was observed in the gastric mucosa of corpus and antrum, in duodenum, jejunum and ileum, while no signal was detected in the colon. Preabsorption of {sup 125}I-nesfatin-1 with non-labeled nesfatin-1 greatly diminished the autoradiographic signal in the stomach indicating specificity (−32%, p < 0.001). A displacement assay showed an effective concentration by which 50% of {sup 125}I-nesfatin-1 bound to the receptor (EC{sub 50}) in the gastric corpus of 80 pM. Moreover, autoradiography was observed in endocrine tissues including the pituitary, pancreas, adrenal gland, testis and visceral adipose tissue. In addition, also heart, skeletal muscle, lung, liver and kidney showed autoradiographic signals. In the brain, strong {sup 125}I-nesfatin-1 autoradiography was detected in the cortex, paraventricular nucleus of the hypothalamus, area postrema, dorsal motor nucleus of the vagus nerve and cerebellum. Based on the distribution of nesfatin-1 autoradiography, nesfatin-1 is a pleiotropic hormone that is involved in the regulation of several homeostatic functions. - Highlights: • Although our knowledge on nesfatin-1 is increasing, the receptor is still unknown. • {sup 125}I-nesfatin-1 autoradiography was detected in (a.o.) the stomach and pancreas. • Central signals were observed in the hypothalamic paraventricular and dorsal motor nucleus. • Distribution data support the notion of nesfatin-1 being a pleiotropic hormone.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Sterol regulatory element binding protein 1 trans-activates 25-hydroxy vitamin D3 24-hydroxylase gene expression in renal proximal tubular cells

Highlights: • SREBP1 activates CYP24A1 transcription in a kidney proximal tubule cell line. • SREBP1 binds to a putative SRE in mouse Cyp24a1 to activate transcription. • Mice injected with thyroid hormone T{sub 3} had reduced renal Srebp1c and Cyp24a1 levels. • SREBP1 trans-activation of CYP24A1 expression could regulate vitamin D{sub 3} levels. The physiological activity of the steroid derived hormone vitamin D is regulated by several enzymatic steps. Both 25-hydroxy vitamin D{sub 3} 1α-hydroxylase (CYP27B1) and 25-hydroxyvitamin D{sub 3} 24-hydroxylase (CYP24A1) modulate blood levels of 1,25-dihydroxyvitamin D{sub 3}, an activated form of vitamin D. We previously demonstrated that CYP27B1 expression was trans-activated by sterol regulatory element binding protein 1 (SREBP1), although whether SREBP1 also regulates CYP24A1 transcription was unclear. Here we investigated the ability of SREBP1 to affect CYP24A1 transcription. In a luciferase reporter assay, mouse and human CYP24A1 promoter activity was strongly activated by SREBP1 in opossum kidney proximal tubular cells (OK-P). Three putative SREs (pSREs) were found in the mouse Cyp24a1 gene promoter and the SREBP1 protein showed specific binding to the pSRE1 element in EMSAs. Site-directed mutagenesis of the pSRE1 element strongly decreased SREBP1-mediated Cyp24a1 gene transcription. Moreover, siRNA-mediated SREBP1 knock-down repressed CYP24A1 expression in human renal proximal tubular epithelial cells (HKC-8). In animal studies, mice given various doses of thyroid hormone (T{sub 3}) showed dose-dependent reductions in renal Srebp1c and Cyp24a1 mRNA levels. Taken together, our results suggest that SREBP1 trans-activates CYP24A1 expression through SREBP binding elements present in the promoter.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Interaction between deca-BDE and hepatic deiodinase in a highly PBDE-exposed bird

Highlights: • Ring-billed gulls breeding in Montreal area are highly exposed to deca-BDE. • We studied biotransformation of deca-BDE and interaction with deiodinases. • No in vitro degradation of deca-BDE was observed using liver microsomes. • Deca-BDE interacted with deiodinase activity at the medium concentration. • Liver deca-BDE concentrations were correlated with plasma thyroid hormone levels. Studies have shown that debromination of the major component in the deca-brominated diphenyl ether mixture (deca-BDE), BDE-209, occurs in vivo in birds. Recent work from our laboratory on breeding ring-billed gulls (Larus delawarensis) exposed to elevated PBDE concentrations in the densely-populated metropolis of Montreal (Canada) further suggests that BDE-209 debromination is potentially catalyzed by deiodinases in liver microsomes. The first objective of this study was to determine if type 1 deiodinase (D1) was involved in the in vitro debromination of BDE-209 in liver microsomes of ring-billed gulls. The second objective was to determine if there was an interaction between D1 and BDE-209 using an in vitro D1 activity assay. No depletion of BDE-209 was observed in gull liver microsomes. A significant 42% increase in total D1 activity was found in gull liver microsomes at the medium BDE-209 concentration (1.0 nM), although not at the low (0.5 nM) or high (2.5 nM) concentrations, suggesting potential non-dose related interaction with D1. Moreover, no correlation was found between total D1 activity in liver microsomes and plasma thyroid hormone levels, although there was a negative relationship between plasma BDE-209 concentrations and FT{sub 3} levels. Results from this study suggest that debromination of BDE-209 did not occur using present in vitro assay conditions, although indicated potential interaction with D1 that may have implication on circulating thyroid hormone status.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2011

Health-Related Quality of Life After Single-Fraction High-Dose-Rate Brachytherapy and Hypofractionated External Beam Radiotherapy for Prostate Cancer

Purpose: To investigate the change in health-related quality of life for men after high-dose-rate brachytherapy and external beam radiotherapy for prostate cancer and the factors associated with this change. Methods and Materials: Eligible patients had clinically localized intermediate-risk prostate cancer. The patients received high-dose-rate brachytherapy as a single 15-Gy implant, followed by external beam radiotherapy to 37.5 Gy in 15 fractions. The patients were monitored prospectively for toxicity (Common Terminology Criteria for Adverse Events, version 3.0) and health-related quality of life (Expanded Prostate Cancer Index Composite [EPIC]). The proportion of patients developing a clinically significant difference in the EPIC domain score (minimally important difference of >0.5 standard deviation) was determined and correlated with the baseline clinical and dosimetric factors. The study accrued 125 patients, with a median follow-up of 24 months. Results: By 24 months, 23% had Grade 2 urinary toxicity and only 5% had Grade 2 bowel toxicity, with no Grade 3 toxicity. The proportion of patients reporting a significant decrease in EPIC urinary, bowel, sexual, and hormonal domain scores was 53%, 51%, 45%, and 40% at 12 months and 57%, 65%, 51%, and 30% at 24 months, respectively. The proportion with a >1 standard deviation decrease in the EPIC urinary, bowel, sexual, and hormonal domain scores was 38%, 36%, 24%, and 20% at 12 months and 46%, 48%, 19%, and 8% at 24 months, respectively. On multivariate analysis, the dose to 10% of the urethra was associated with a decreasing EPIC urinary domain score (p = .0089) and, less strongly (p = .0312) with a decreasing hormonal domain score. No association was found between the prostate volume, bladder dose, or high-dose volume and urinary health-related quality of life. A high baseline International Index of Erectile Function score was associated (p = .0019) with a decreasing sexual domain score. The optimal maximal dose to 10% of the urethra cutpoint for urinary health-related quality of life was 120% of the prescription dose. Conclusion: EPIC was a more sensitive tool for detecting the effects on function and bother than were the generic toxicity scales. The urethral dose had the strongest association with a deteriorating urinary quality of life.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2011

Multi-Institutional Phase II Study of Proton Beam Therapy for Organ-Confined Prostate Cancer Focusing on the Incidence of Late Rectal Toxicities

Purpose: Proton beam therapy (PBT) is theoretically an excellent modality for external beam radiotherapy, providing an ideal dose distribution. However, it is not clear whether PBT for prostate cancer can clinically control toxicities. The purpose of the present study was to estimate prospectively the incidence of late rectal toxicities after PBT for organ-confined prostate cancer. Methods and Materials: The major eligibility criteria included clinical Stage T1-T2N0M0; initial prostate-specific antigen level of {<=}20 ng/mL and Gleason score {<=}7; no hormonal therapy or hormonal therapy within 12 months before registration; and written informed consent. The primary endpoint was the incidence of late Grade 2 or greater rectal toxicity at 2 years. Three institutions in Japan participated in the present study after institutional review board approval from each. PBT was delivered to a total dose of 74 GyE in 37 fractions. The patients were prospectively followed up to collect the data on toxicities using the National Cancer Institute-Common Toxicity Criteria, version 2.0. Results: Between 2004 and 2007, 151 patients were enrolled in the present study. Of the 151 patients, 75, 49, 9, 17, and 1 had Stage T1c, T2a, T2b, T2c, and T3a, respectively. The Gleason score was 4, 5, 6, and 7 in 5, 15, 80 and 51 patients, respectively. The initial prostate-specific antigen level was <10 or 10-20 ng/mL in 102 and 49 patients, respectively, and 42 patients had received hormonal therapy and 109 had not. The median follow-up period was 43.4 months. Acute Grade 2 rectal and bladder toxicity temporarily developed in 0.7% and 12%, respectively. Of the 147 patients who had been followed up for >2 years, the incidence of late Grade 2 or greater rectal and bladder toxicity was 2.0% (95% confidence interval, 0-4.3%) and 4.1% (95% confidence interval, 0.9-7.3%) at 2 years, respectively. Conclusion: The results of the present prospective study have revealed a valuable piece of evidence that PBT for localized prostate cancer can achieve a low incidence of late Grade 2 or greater rectal toxicities.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2016

Can Angiotensin-Converting Enzyme Inhibitors Reduce the Incidence, Severity, and Duration of Radiation Proctitis?

Purpose: To determine whether participants taking angiotensin-converting enzyme inhibitors (ACEIs) and treated with radical radiation therapy with neoadjuvant/adjuvant hormone therapy have less incidence, severity, and duration of radiation proctitis. Methods and Materials: A propensity score analysis of 817 patients who underwent radical radiation therapy with neoadjuvant or adjuvant hormone therapy as primary line management in a cohort study during 2009 to 2013 was conducted. Patients were stratified as follows: group 1, hypertensive patients taking ACEIs (as a study group); group 2, nonhypertensive patients not taking ACEIs; and group 3, hypertensive patients not taking ACEIs (both as control groups). The incidence, severity, and duration of proctitis were the main outcome. χ{sup 2} tests, Mann-Whitney U tests, analysis of variance, risk ratio (RR), confidence interval (CI), Kaplan-Meier plots, and log-rank tests were used. Results: The mean age of the participants was 68.91 years, with a follow-up time of 3.38 years. Based on disease and age-matched comparison, there was a statistically significant difference of proctitis grading between the 3 groups: χ{sup 2} (8, n=308) = 72.52, P<.001. The Mann-Whitney U test indicated that grades of proctitis were significantly lower in hypertensive patients taking ACEIs than in nonhypertensive patients not taking ACEIs and hypertensive patients not taking ACEIs (P<.001). The risk ratio (RR) of proctitis in hypertensive patients taking ACEIs was significantly lower than in hypertensive patients not taking ACEIs (RR 0.40, 95% CI 0.30-0.53, P<.001) and in nonhypertensive patients not taking ACEIs (RR 0.58, 95% CI 0.44-0.77, P<.001). Time to event analysis revealed that hypertensive patients taking ACEIs were significantly different from the control groups (P<.0001). Furthermore, hypertensive patients taking ACEIs had significantly faster resolution of proctitis (P<.0001). Conclusion: Patients who were taking ACEIs were significantly less likely to have high-grade proctitis after radical radiation therapy with neoadjuvant or adjuvant hormone therapy (P<.001). The intake of ACEIs was significantly associated with a reduced risk of radiation-induced proctitis and also with acceleration of its resolution.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2026

Acute wood smoke exposure is associated with cell-specific hippocampal transcriptomic responses in an accelerated ovarian failure mouse model

Background Wildfire events are increasing in frequency and intensity, and aging individuals demonstrate heightened biological susceptibility to air pollution exposures including increased risk of neurological sequelae. Declining ovarian hormones levels that occur with aging in females along with associated systemic physiological and inflammatory changes may contribute to increased cerebral vulnerability to air pollution, representing a potential but underexplored mechanism. Menopause and the menopausal transition represent a period of profound physiological change that affects cardiovascular, neurological, and immune health. Methods We tested whether peri-menopausal–like hormonal status amplifies hippocampal responses to acute wood smoke (WS) using an ovary-intact, 4-vinylcyclohexene diepoxide (VCD) model of moderate accelerated ovarian failure (AOF) in female C57BL/6 mice. Animals were exposed to HEPA-filtered air (FA) or WS for 4 h/day over 2 consecutive days (∼0.5 mg/m³). Exposure characterization confirmed a complex mixture of combustion products with significant levels of both trace metals and gas release during WS exposure. Results Spatial transcriptomics (10x Visium; n = 4 sections/group) with automated cell-type annotation identified astrocytes, GABAergic and glutamatergic neurons, oligodendrocytes, revealed cell type-specific transcriptional alterations following WS exposure. Distinct transcriptional patterns were observed across all identified neuronal and glial cell populations. Conclusion Together, these findings define a cell-type specific transcriptomic framework describing how WS exposure and ovarian hormone decline interact to influence hippocampal responses and identify potential cellular pathways relevant to hippocampal vulnerability.

63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTAN↗
DOE OSTI2012

Hydroxylated PBDEs induce developmental arrest in zebrafish

The ubiquitous spread of polybrominated diphenyl ethers (PBDEs) has led to concerns regarding the metabolites of these congeners, in particular hydroxylated PBDEs. There are limited studies regarding the biological interactions of these chemicals, yet there is some concern they may be more toxic than their parent compounds. In this study three hydroxylated PBDEs were assessed for toxicity in embryonic zebrafish: 3-OH-BDE 47, 5-OH-BDE 47, and 6-OH-BDE 47. All three congeners induced developmental arrest in a concentration-dependent manner; however, 6-OH-BDE 47 induced adverse effects at lower concentrations than the other congeners. Furthermore, all three induced cell death; however apoptosis was not observed. In short-term exposures (24–28 hours post fertilization), all hydroxylated PBDEs generated oxidative stress in the region corresponding to the cell death at 5 and 10 ppm. To further investigate the short-term effects that may be responsible for the developmental arrest observed in this study, gene regulation was assessed for embryos exposed to 0.625 ppm 6-OH-BDE 47 from 24 to 28 hpf. Genes involved in stress response, thyroid hormone regulation, and neurodevelopment were significantly upregulated compared to controls; however, genes related to oxidative stress were either unaffected or downregulated. This study suggests that hydroxylated PBDEs disrupt development, and may induce oxidative stress and potentially disrupt the cholinergic system and thyroid hormone homeostasis. -- Highlights: ► OH-PBDEs induce developmental arrest in a concentration-dependent manner. ► Hydroxyl group location influences biological interaction. ► OH-PBDEs induce oxidative stress. ► Thyroid hormone gene regulation was disrupted following exposure. ► To our knowledge, this is the first whole organism study of OH-PBDE toxicity.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

Effects of the UV filter benzophenone-3 (oxybenzone) at low concentrations in zebrafish (Danio rerio)

Organic UV filters including benzophenone-3 (BP-3) are widely used to protect humans and materials from damage by UV irradiation. Despite the environmental occurrence of BP-3 in the aquatic environment, little is known about its effects and modes of action. In the present study we assess molecular and physiological effects of BP-3 in adult male zebrafish (Danio rerio) and in eleuthero-embryos by a targeted gene expression approach focusing on the sex hormone system. Fish and embryos are exposed for 14 days and 120 hours post fertilization, respectively, to 2.4–312 μg/L and 8.2–438 μg/L BP-3. Chemical analysis of water and fish demonstrates that BP-3 is partly transformed to benzophenone-1 (BP-1) and both compounds are accumulated in adult fish. Biotransformation to BP-1 is absent in eleuthero-embryos. BP-3 exposure leads to similar alterations of gene expression in both adult fish and eleuthero-embryos. In the brain of adult males esr1, ar and cyp19b are down-regulated at 84 μg/L BP-3. There is no induction of vitellogenin expression by BP-3, both at the transcriptional and protein level. An overall down-regulation of the hsd3b, hsd17b3, hsd11b2 and cyp11b2 transcripts is observed in the testes, suggesting an antiandrogenic activity. No histological changes were observed in the testes after BP-3 treatment. The study leads to the conclusion that low concentrations of BP-3 exhibit similar multiple hormonal activities at the transcription level in two different life stages of zebrafish. Forthcoming studies should show whether this translates to additional physiological effects. Highlights: ► Activity of UV filter benzophenone-3 (BP-3) is assessed in zebrafish. ► BP-3 is partly metabolized to benzophenone-1 by adult fish but not embryos. ► Alterations of gene expression are similar in adult males and embryos. ► Gene expression alterations point to multiple hormonal activity of BP-3.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

2,3,4,7,8-Pentachlorodibenzofuran is far less potent than 2,3,7,8-tetrachlorodibenzo-p-dioxin in disrupting the pituitary–gonad axis of the rat fetus

The effect of 2,3,4,7,8-pentachlorodibenzofuran (PnCDF) on the fetal pituitary–gonad axis was compared with that produced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in Wistar rats. Maternal treatment at gestational day (GD) 15 with PnCDF and TCDD reduced the fetal expression at GD20 of pituitary luteinizing hormone (LH) and the testicular proteins necessary for steroidogenesis. The relative potencies of PnCDF ranged from 1/42nd to 1/63rd of the TCDD effect. While PnCDF, at a dose sufficient to cause a reduction in fetal LH, provoked defects in sexual behavior at adulthood, a dose less than the ED{sub 50} failed to produce any abnormality. There was a loss of fetal body weight following in utero exposure to PnCDF, and the effect of PnCDF was also much less than that of TCDD. The disturbance in fetal growth was suggested to be due to a reduction in the level of fetal growth hormone (GH) by dioxins. The disorder caused by PnCDF/TCDD in the fetal pituitary–gonad axis occurred at doses less than those needed to cause wasting syndrome in pubertal rats. The harmful effect of PnCDF relative to TCDD was more pronounced in fetal rats than in pubertal rats. These lines of evidence suggest that: 1) PnCDF as well as TCDD imprints defects in sexual behavior by disrupting the fetal pituitary–gonad axis; 2) these dioxins hinder fetal growth by reducing the expression of fetal GH; and 3) the fetal effects of PnCDF/TCDD are more sensitive than sub-acute toxicity during puberty, and the relative effect of PnCDF varies markedly depending on the indices used. - Highlights: • 2,3,4,7,8-Pentachlorodibenzofuran (PnCDF) lowers gonadal steroidogenesis in fetuses. • PnCDF exerts the above effect through an initial attenuation in gonadotropin level. • PnCDF imprints sexual immaturity by transiently disrupting the pituitary–gonad axis. • PnCDF also disturbs pup growth probably due to a reduction in growth hormone level. • The above effects are far lesser in PnCDF than 2,3,7,8-tetrachlorodibenzo-p-dioxin.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

The contribution of the neuroendocrine system to adaption after repeated daily ozone exposure in rats

Ozone-induced lung injury/inflammation dissipates despite continued exposure for 3 or more days; however, the mechanisms of adaptation/habituation remain unclear. Since ozone effects are mediated through adrenal-derived stress hormones, which also regulate longevity of centrally-mediated stress response, we hypothesized that ozone-adaptation is linked to diminution of neuroendocrine stress-axes activation and glucocorticoid levels. Male Wistar-Kyoto-rats (12-week-old) were injected with vehicle or a therapeutically-relevant dexamethasone dose (0.01-mg/kg/day; intraperitoneal) for 1-month to determine if suppression of glucocorticoid signaling was linked to adaptation. Vehicle- and dexamethasone-treated rats were exposed to air or 0.8-ppm ozone, 4 h/day × 2 or 4 days to assess the impacts of acute exposure and adaptation, respectively. Dexamethasone reduced thymus and spleen weights, circulating lymphocytes, corticosterone and increased insulin. Ozone increased lavage-fluid protein and neutrophils and decreased circulating lymphocytes at day-2 but not day-4. Ozone-induced hyperglycemia, glucose intolerance and inhibition of beta-cell insulin release occurred at day-1 but not day-3. Ozone depleted circulating prolactin, thyroid-stimulating hormone, and luteinizing-hormone at day-2 but not day-4, suggesting central mediation of adaptation. Adrenal epinephrine biosynthesis gene, Pnmt, was up-regulated after ozone exposure at both timepoints. However, genes involved in glucocorticoid biosynthesis were up-regulated after day-2 but not day-4, suggesting that acute 1- or 2-day ozone-mediated glucocorticoid increase elicits feedback inhibition to dampen hypothalamic stimulation of ACTH release in response to repeated subsequent ozone exposures. Although dexamethasone pretreatment affected circulating insulin, lymphocytes and adrenal genes, it had modest effect on ozone adaptation. In conclusion, ozone adaptation likely involves lack of hypothalamic response due to reduced availability of circulating glucocorticoids.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Disordered Structural Ensembles of Vasopressin and Oxytocin and Their Mutants

Vasopressin and oxytocin are intrinsically disordered cyclic nonapeptides belonging to a family of neurohypophysial hormones. Although unique in their functions, these peptides differ only by two residues and both feature a tocin ring formed by the disulfide bridge between first and sixth cysteine residues. This sequence and structural similarity are experimentally linked to oxytocin agonism at vasopressin receptors and vasopressin antagonism at oxytocin receptors. Yet single- or double-residue mutations in both peptides have been shown to have drastic impacts on their activities at either receptor, and possibly the ability to bind to their neurophysin carrier protein. In this study we perform molecular dynamics simulations of the unbound native and mutant sequences of the oxytocin and vasopressin hormones to characterize their structural ensembles. We classify the subpopulations of these structural ensembles on the basis of the distributions of radius of gyration and secondary structure and hydrogen-bonding features of the canonical tocin ring and disordered tail region. We then relate the structural changes observed in the unbound form of the different hormone sequences to experimental information about peptide receptor binding, and more indirectly, carrier protein binding affinity, receptor activity, and protease degradation. Here, this study supports the hypothesis that the structural characteristics of the unbound form of an IDP can be used to predict structural or functional preferences of its functional bound form.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2023

Assessing variation in faecal glucocorticoid concentrations in gray whales exposed to anthropogenic stressors

Understanding how individual animals respond to stressors behaviourally and physiologically is a critical step towards quantifying long-term population consequences and informing management efforts. Glucocorticoid (GC) metabolite accumulation in various matrices provides an integrated measure of adrenal activation in baleen whales and could thus be used to investigate physiological changes following exposure to stressors. In this study, we measured GC concentrations in faecal samples of Pacific Coast Feeding Group (PCFG) gray whales (Eschrichtius robustus) collected over seven consecutive years to assess the association between GC content and metrics of exposure to sound levels and vessel traffic at different temporal scales, while controlling for contextual variables such as sex, reproductive status, age, body condition, year, time of year and location. We develop a Bayesian Generalized Additive Modelling approach that accommodates the many complexities of these data, including non-linear variation in hormone concentrations, missing covariate values, repeated samples, sampling variability and some hormone concentrations below the limit of detection. Estimated relationships showed large variability, but emerging patterns indicate a strong context-dependency of physiological variation, depending on sex, body condition and proximity to a port. Our results highlight the need to control for baseline hormone variation related to context, which otherwise can obscure the functional relationship between faecal GCs and stressor exposure. Therefore, extensive data collection to determine sources of baseline variation in well-studied populations, such as PCFG gray whales, could shed light on cetacean stress physiology and be used to extend applicability to less-well-studied taxa. GC analyses may offer greatest utility when employed as part of a suite of markers that, in aggregate, provide a multivariate measure of physiological status, better informing estimates of individuals’ health and ultimately the consequences of anthropogenic stressors on populations.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Ectomycorrhizal symbiosis prepares its host locally and systemically for abiotic cue signaling

Tree growth and survival are dependent on their ability to perceive signals, integrate them, and trigger timely and fitted molecular and growth responses. While ectomycorrhizal symbiosis is a predominant tree-microbe interaction in forest ecosystems, little is known about how and to what extent it helps trees cope with environmental changes. We hypothesized that the presence of Laccaria bicolor influences abiotic cue perception by Populus trichocarpa and the ensuing signaling cascade. We submitted ectomycorrhizal or non-ectomycorrhizal P. trichocarpa cuttings to short-term cessation of watering or ozone fumigation to focus on signaling networks before the onset of any physiological damage. Poplar gene expression, metabolite levels, and hormone levels were measured in several organs (roots, leaves, mycorrhizas) and integrated into networks. We discriminated the signal responses modified or maintained by ectomycorrhization. Ectomycorrhizas buffered hormonal changes in response to short-term environmental variations systemically prepared the root system for further fungal colonization and alleviated part of the root abscisic acid (ABA) signaling. Furthermore, the presence of ectomycorrhizas in the roots also modified the leaf multi-omics landscape and ozone responses, most likely through rewiring of the molecular drivers of photosynthesis and the calcium signaling pathway. In conclusion, P. trichocarpa-L. bicolor symbiosis results in a systemic remodeling of the host's signaling networks in response to abiotic changes. In addition, ectomycorrhizal, hormonal, metabolic, and transcriptomic blueprints are maintained in response to abiotic cues, suggesting that ectomycorrhizas are less responsive than non-mycorrhizal roots to abiotic challenges.

60 APPLIED LIFE SCIENCES↗