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All sources NASA NTRS DOE OSTI

DOE OSTI2017

Genistein prevention of hyperglycemia and improvement of glucose tolerance in adult non-obese diabetic mice are associated with alterations of gut microbiome and immune homeostasis

Although studies have linked soy phytoestrogen 4,7,4-trihydroxyisoflavone genistein (GEN) to reduced type 1 diabetes (T1D) risk, the mechanism of dietary GEN on T1D remains unknown. In our studies, adult non-obese diabetic (NOD) mouse model was employed to investigate the effects of GEN exposure on blood glucose level (BGL), glucose tolerance, gut microbiome, and immune responses. Adult male and female NOD mice were fed with either soy-based or casein-based diet, and received GEN at 20 mg/kg body weight by gavage daily. The BGL and immune responses (represented by serum antibodies, cytokines and chemokines, and histopathology) were monitored, while the fecal gut microbiome was sequenced for 16S ribosomal RNA to reveal any alterations in gut microbial communities. A significantly reduced BGL was found in NOD males fed with soy-based diet on day 98 after initial dosing, and an improved glucose tolerance was observed on both diets. In addition, an anti-inflammatory response (suggested by reduced IgG{sub 2b} and cytokine/chemokine levels, and alterations in the microbial taxonomy) was accompanied by an altered β-diversity in gut microbial species. Among the NOD females exposed to GEN, a later onset of T1D was observed. However, the profiles of gut microbiome, antibodies and cytokines/chemokines were all indicative of pro-inflammation. This study demonstrated an association among GEN exposure, gut microbiome alteration, and immune homeostasis in NOD males. Although the mechanisms underlying the protective effects of GEN in NOD mice need to be explored further, the current study suggested a GEN-induced sex-specific effect in inflammatory status and gut microbiome. - Highlights: • GEN reduces blood glucose level and improves glucose tolerance in NOD males. • GEN delayed type 1 diabetes onset in NOD females. • GEN produces a perturbed gut microbiota in both NOD males and females. • GEN produces anti-inflammatory responses in NOD males. • GEN produces pro-inflammatory responses in NOD females.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2024

Incidence and predictors of loss to follow-up among adult patients receiving antiretroviral therapy in Central Ethiopia: a multi-center retrospective cohort study

Background: Globally, loss to follow-up (LTFU) remains a significant public health concern despite the rapid expansion of antiretroviral medication programs. It is a significant cause of treatment failure and threatens the enhancement of HIV treatment outcomes among patients on antiretroviral therapy (ART). However, there is a paucity of evidence on its incidence and predictors in Ethiopia. Thus, this study aimed to examine the incidence and predictors of LTFU among adult HIV patients receiving ART at hospitals in Central Ethiopia. Methods: A multi-centered facility-based retrospective cohort study was conducted among 432 randomly selected adult patients who received antiretroviral therapy. Data were entered into EpiData version 3.1 and exported to Stata version 14 for analysis. The Kaplan–Meier failure function was employed to determine the overall failure estimates, and the log-rank test was used to compare the probability of failure among the different categories of variables. The Cox proportional hazard model was used to identify independent predictors of LTFU. Results: Overall, 172 (39.8%) study participants were lost to follow-up over the 10-year follow-up period with an incidence rate of 8.12 (95% CI: 7.11, 9.09) per 1,000 person-months. Undisclosed HIV status (AHR: 1.96, 95% CI: 1.14, 3.36), not able to work (AHR: 1.84, 95% CI: 1.13, 2.22), opportunistic infections (AHR: 3.13, 95% CI: 2.17, 4.52), CD4 < 200 cell/mL (AHR: 1.95, 95% CI: 1.18, 3.21), not receiving isoniazid preventive therapy (IPT) (AHR: 2.57, 95% CI: 1.62, 4.06), not participating in clubs (AHR: 1.68, 95% CI: 1.10, 2.22), side effects of drugs (AHR: 1.44, 95% CI: 1.02, 2.04), and high viral load (AHR: 3.15, 95% CI: 1.81, 5.47) were identified as significant predictors of loss to follow-up. Conclusion: In this study, the incidence of LTFU was high. The focus should be on creating awareness and prevention programs that aim to reduce loss to follow-up by continuing counseling, especially on the negative effects of loss to follow-up and the benefits of ART care.

60 APPLIED LIFE SCIENCES↗

NASA NTRS2003

The dynamics of herpesvirus and polyomavirus reactivation and shedding in healthy adults: a 14-month longitudinal study

Humans are infected with viruses that establish long-term persistent infections. To address whether immunocompetent individuals control virus reactivation globally or independently and to identify patterns of sporadic reactivation, we monitored herpesviruses and polyomaviruses in 30 adults, over 14 months. Epstein-Barr virus (EBV) DNA was quantitated in saliva and peripheral blood mononuclear cells (PBMCs), cytomegalovirus (CMV) was assayed in urine, and JC virus (JCV) and BK virus (BKV) DNAs were assayed in urine and PBMCs. All individuals shed EBV in saliva, whereas 67% had >or=1 blood sample positive for EBV. Levels of EBV varied widely. CMV shedding occurred infrequently but occurred more commonly in younger individuals (P<.03). JCV and BKV virurias were 46.7% and 0%, respectively. JCV shedding was age dependent and occurred commonly in individuals >or=40 years old (P<.03). Seasonal variation was observed in shedding of EBV and JCV, but there was no correlation among shedding of EBV, CMV, and JCV (P>.50). Thus, adults independently control persistent viruses, which display discordant, sporadic reactivations.

Non-NASA Center↗

DOE OSTI2021

Pulmonary ACE2 expression in neonatal and adult rats

Children show a distinct presentation of COVID‐19, characterized by a lower incidence and mild phenotype, but the reason for this is still unknown. The angiotensin‐converting enzyme 2 (ACE2) functions as the primary cell entry receptor for Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and is thought to cause distinct clinical features between children and old people. The primary purpose of this study was to determine whether differences exist in the level of expression and distribution of ACE2 between neonatal and adult rat lungs. The lung tissues from rats of various ages were used to investigate the expression patterns of ACE2. Western blot, immunohistochemistry, and immunofluorescence were used to quantify or identify the localization of ACE2 in rat lungs. ACE2 was homogenously expressed in fewer alveolar type II (AT2) cells in the neonatal lung, with no polarization to the alveolar space and additional expression in pulmonary endothelium when compared to adult rat lungs. These findings suggest that the patterns of ACE2 distribution and cellular localization in rat lungs change with age.

Zhao, Depeng↗

DOE OSTI2019

Adult height, body mass index change, and body shape change in relation to esophageal squamous cell carcinoma risk: A population‐based case‐control study in China

Abstract The relationship between risk of esophageal squamous cell carcinoma (ESCC) and adult height, changes in individual body mass index (BMI) and body shape is not established. We performed a large population‐based case‐control study, which enrolled a total of 1414 ESCC cases and 1989 controls in a high‐incidence area in China. Using face‐to‐face interview with a structured questionnaire, information on participants' heights, weights, and perceived body shapes at 20 years of age was collected. Additionally, data on weight and perceived body shape among the same participants 10 years prior to ascertainment were collected using the same method. Odd ratios (ORs) of ESCC risk in relation to BMI and body shape were estimated using unconditional logistic regression models. The adjusted results indicated that ESCC risk in adults rapidly rose as height increased, plateauing at 170 cm among men and 157 cm among women. Among participants who were underweight, normal weight, or thinner than body shape 4, body weight loss was associated with increased risk of ESCC, and body weight gain was associated with decreased incidence of ESCC (ORs ranging from 0.40 to 0.76). Notably, however, changes in body weight did not significantly affect ESCC risk among participants who were overweight, obese, or larger than body shape 3. Maintaining a fit body shape and a reasonable BMI is advisable and of vital importance to reduce the risk of ESCC, especially in high‐risk areas.

Yang, Xiaorong↗

DOE OSTI2018

Winter-Rearing Temperature Affects Growth Profiles, Age of Maturation, and Smolt-to-Adult Returns for Yearling Summer Chinook Salmon in the Upper Columbia River Basin

Abstract We assessed the effects of rearing conditions in four hatchery programs from the upper Columbia River basin on the survival and demographics of yearling summer Chinook Salmon Oncorhynchus tshawytscha over four release years. Juveniles from each hatchery program were initially reared at Eastbank Hatchery near Wenatchee, Washington, (which uses groundwater for fish rearing) and experienced similar rearing temperatures until their first autumn in culture. Fish that were to be used for two of the programs were subsequently transferred to surface water acclimation sites, where they were reared until release the following spring (surface water winter rearing). Fish to be used for the other two programs were overwintered at the Eastbank Hatchery and then transferred to their acclimation and release sites 1 to 2 months before spring release (groundwater winter rearing). Fish from the two rearing strategies experienced contrasting temperature profiles, which in turn affected winter growth, age at maturation, and smolt-to-adult survival (SAS). Overall, the two release groups that were overwintered in colder surface water experienced reduced winter growth, reduced minijack rate, and smaller size at release, but achieved a two- to threefold higher SAS than did the two release groups overwintered in warmer groundwater at Eastbank Hatchery. In addition, based on migration data compiled from fish tagged with PIT tags, smaller juveniles tended to mature at older age-classes than did larger smolts. We concluded that rearing yearling hatchery summer Chinook Salmon under more natural thermal regimes (surface water) may result in the return of larger, older adults that have a higher survival rate than would fish reared under constant or less natural thermal regimes (ground water). These results highlight the importance of the hatchery-rearing environment in shaping the survival and life history of summer Chinook Salmon juveniles released into the Columbia River basin.

Harstad, Deborah L.↗

DOE OSTI2019

Single institutional experience with initial ultrasound followed by computed tomography or magnetic resonance imaging for acute appendicitis in adults

Purpose: The objectives of this study was to assess the performance of ultrasound (US) for suspected appendicitis in adult patients and to evaluated the additive value of short-interval (within 1 week) computed tomography (CT) or Magnetic Resonance Imaging (MRI) after performing an initial US. Methods: In this IRB-approved, HIPAA-compliant, retrospective study, electronic medical records (EMRs) were queried for “US appendicitis” performed over a 2-year interval. EMR was reviewed for CT or MRI performed within 1 week of this exam, and if any new or additional information was available at subsequent exam. White count, patient disposition, and pathology, if surgery was performed, were also recorded. Results: 682 patients underwent US for appendicitis over a 2-year duration, age range from 18 to 92 years (average: 30.1 years, M:F = 141:541). Findings showed 126/682 patients with normal appendix, 75/682 uncomplicated appendicitis, and 4/682 with complicated appendicitis. When performed, no additional findings were seen in these groups on short-interval CT or MRI. 2/682 patients had equivocal findings on US but eventually had normal appendix identified on CT. Four hundred and seventy-three patients had non-visualized appendix, of which only 14/473 (3.1%) eventually had appendicitis. Conclusions: Ultrasound is an effective initial modality for evaluating appendicitis even in adult patients. Once a normal appendix, uncomplicated or complicated appendicitis is identified on US, no further imaging is necessary. Very few patients with non-visualization of the appendix eventually have appendicitis. Hence, these patients can be managed with active clinical follow-up rather than immediate CT or MRI. Symptoms and clinical scoring systems can be used for triage of these patients.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2014

Rigidity and resistance of larval- and adult schistosomes-medium interface

Graphical abstract: - Highlights: • Schistosoma larvae and worms are studied by neutron scattering. • Measurements on larvae were repeated after one day and by increasing temperature. • The flexibility properties of larvae and adult parasites are compared. • The parasite rigidity is related to their resistance to the hostile environment. • Insight into the parasite defense mechanisms to the immune system attack is achieved. - Abstract: Schistosomiasis is second only to malaria in prevalence and severity, and is still a major health problem in many tropical countries worldwide with about 200–300 million cases and with more than 800 million people at risk of infection. Based on these data, the World Health Organization recommends fostering research efforts for understanding at any level the mechanisms of the infection and then decreasing the social and economical impact of schistosomiasis. A key role is played by the parasite apical lipid membrane, which is entirely impervious to the surrounding elements of the immune system. We have previously demonstrated that the interaction between schistosomes and surrounding medium is governed by a parasite surface membrane sphingomyelin-based hydrogen barrier. In the present article, the elastic contribution to the total motion as a function of the exchanged wave-vector Q and the mean square displacement values for Schistosoma mansoni larvae and worms and Schistosomahaematobium worms have been evaluated by quasi elastic neutron scattering (QENS). The results point out that S. mansoni larvae show a smaller mean square displacement in comparison to S. mansoni and S. haematobium worms. These values increased by repeating the measurements after one day. These differences, which are analogous to those observed for the diffusion coefficient we previously evaluated, are interpreted in terms of rigidity of the parasite-medium interaction. S. mansoni larvae are the most rigid systems, while S. haematobium worms are the most flexible. In addition, temperature and hypoxia induce a weakening of the schistosome-medium interaction. These evidences are related to the strength of the hydrogen-bonded interaction between parasites and environment that we previously determined. We have shown that S. mansoni worms are characterized by a weakened interaction in respect to the larvae, while the S. haematobium worms more weakly interact with the surrounding medium than S. mansoni. The present QENS analysis allowed us to characterize the rigidity of larval- and adult S. mansoni and S. haematobium-host interface and to relate it to the parasite resistance to the hostile elements of the surrounding medium and to the immune effectors attack.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

Modulation by orexin A of spontaneous excitatory and inhibitory transmission in adult rat spinal substantia gelatinosa neurons

Highlights: • Orexin A produced membrane depolarization in substantia gelatinosa neurons. • Orexin A increased spontaneous l-glutamate release in substantia gelatinosa neurons. • Orexin A facilitated GABAergic transmission in substantia gelatinosa neurons. • Orexin A facilitated glycinergic transmission in substantia gelatinosa neurons. • All of orexin A activities were due to orexin-1 but not orexin-2 receptor activation. Hypothalamic neuropeptides, orexins A and B, differently inhibit nociceptive behavior. This difference is possibly due to a distinction between orexins A and B in modulating synaptic transmission in spinal substantia gelatinosa (SG) neurons that play a pivotal role in regulating nociceptive transmission. Although we previously reported a modulatory action of orexin B on synaptic transmission in adult rat SG neurons, it has not been fully examined how the transmission is affected by orexin A. The present study examined the effects of orexin A on spontaneous excitatory and inhibitory transmission in SG neurons of adult rat spinal cord slices by using the whole-cell patch-clamp technique. Like orexin B, orexin A produced an inward current at −70 mV and/or increased the frequency of spontaneous excitatory postsynaptic current without changing its amplitude. Half-maximal effective concentration values for their effects were 0.0045 and 0.030 μM, respectively; the former value was four-fold smaller than that of orexin B while the latter value was comparable to that of orexin B. Orexin A enhanced not only glycinergic but also GABAergic transmission, although only glycinergic transmission was facilitated by orexin B in the majority of neurons tested. Orexin A activities were inhibited by an orexin-1 receptor antagonist (SB334867) but not an orexin-2 receptor antagonist (JNJ10397049), as different from orexin B whose activation was depressed by JNJ10397049 but not SB334867. These results indicate that orexin A has a different action from orexin B in SG neurons in efficacy for inward current production and in GABAergic transmission enhancement, possibly owing to orexin-1 but not orexin-2 receptor activation. This difference could contribute to at least a part of the distinction between orexins A and B in antinociceptive effects.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

Osteoblast AMP-activated protein kinase regulates glucose metabolism and bone mass in adult mice

Previous studies have shown that AMP-activated protein kinase (AMPK), a crucial regulator of energy homeostasis, plays important roles in osteoblast differentiation and mineralization. However, little is known about in vivo roles of osteoblastic AMPK in glucose metabolism and bone mass regulation in adult mice. Here, we used the inducible Cre system to control the onset of Ampk disruption after birth by removing doxycycline supplementation. We conditionally inactivated Ampk in osterix (Osx)-expressing cells in 3-week-old Ampk{sup −/−} mice. After 6 months of Ampk inactivation, the Ampk{sup −/−} mice displayed lower serum osteocalcin levels as well as glucose intolerance and insulin resistance, as indicated by glucose tolerance and insulin tolerance tests, respectively, when compared with wild-type mice. After 18 months of Ampk inactivation, micro computed tomography showed significant reductions in trabecular bone volume and cortical bone thickness in the femur of Ampk{sup −/−} mice when compared with wild-type mice. Moreover, bone stiffness was significantly lower in Ampk{sup −/−} mice than in wild-type mice. This is the first study to show that osteoblast AMPK plays an important roles in glucose metabolism and in maintaining trabecular bone volume, cortical thickness, and bone strength in adult mice.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2014

Environmental cadmium and lead exposures and age-related macular degeneration in U.S. adults: The National Health and Nutrition Examination Survey 2005 to 2008

Age-related macular degeneration (AMD) is a complex disease resulting from the interplay of genetic predisposition and environmental exposures, and has been linked to oxidative stress and inflammatory mechanisms. Lead and cadmium can accumulate in human retinal tissues and may damage the retina through oxidative stress, and may thereby play a role in the development of AMD. We examined associations between blood lead, blood cadmium, and urinary cadmium concentrations and the presence of AMD in 5390 participants aged 40 years and older with blood lead and blood cadmium measures and a subsample of 1548 with urinary cadmium measures in the 2005–2008 National Health and Nutrition Examination Surveys. AMD was identified by grading retinal photographs with a modification of the Wisconsin Age-Related Maculopathy Grading System. The weighted prevalence of AMD was 6.6% (n=426). Controlling for age, gender, race/ethnicity, education and body mass index, adults in the highest blood cadmium quartile had higher odds of AMD compared to the lowest quartile (odds ratio [OR], 1.56; 95% CI, 1.02–2.40), with a significant trend across quartiles (p-trend=0.02). After further adjustment for pack-years of cigarette smoking, estimates were somewhat attenuated (OR, 1.43; 95% CI, 0.91–2.27; p-trend=0.08). Similar associations were found with urinary cadmium. The association between urinary cadmium and AMD was stronger in non-Hispanic whites (NHW) than in non-Hispanic blacks (NHB) (OR, 3.31; 95% CI, 1.37–8.01 for levels above versus below the median among NHW; OR,1.45; 95% CI, 0.40–5.32 for levels above versus below the median among NHB; p-interaction=0.03). We found no association between blood lead levels and AMD. Higher cadmium body burden may increase risk of AMD, particularly among non-Hispanic white individuals; however, additional studies are needed before firm conclusions can be drawn. - Highlights: • We examined the association of cadmium and lead with age-related macular degeneration (AMD) in U.S. adults. • Cadmium in both blood and urine was borderline significantly associated with the risk of AMD. • Blood lead was not associated with the risk of AMD. • The association between urine cadmium and AMD was stronger in whites than in blacks.

54 ENVIRONMENTAL SCIENCES↗

DOE OSTI2015

Association of lead and cadmium exposure with frailty in US older adults

Background: Environmental lead and cadmium exposure is associated with higher risk of several age-related chronic diseases, including cardiovascular disease, chronic kidney disease and osteoporosis. These diseases may lead to frailty, a geriatric syndrome characterized by diminished physiologic reserve in multiple systems with decreased ability to cope with acute stressors. However, no previous study has evaluated the association between lead or cadmium exposure and frailty. Methods: Cross-sectional study among individuals aged ≥60 years who participated in the third U.S. National Health and Nutrition Examination Survey and had either blood lead (N=5272) or urine cadmium (N=4887) determinations. Frailty was ascertained with a slight modification of the Fried criteria, so that individuals meeting ≥3 of 5 pre-defined criteria (exhaustion, low body weight, low physical activity, weakness and slow walking speed), were considered as frail. The association between lead and cadmium with frailty was evaluated using logistic regression with adjustment for relevant confounders. Results: Median (intertertile range) concentrations of blood lead and urine cadmium were 3.9 µg/dl (2.9–4.9) and 0.62 µg/l (0.41–0.91), respectively. The prevalence of frailty was 7.1%. The adjusted odds ratios (95% confidence interval) of frailty comparing the second and third to the lowest tertile of blood lead were, respectively, 1.40 (0.96–2.04) and 1.75 (1.33–2.31). Lead concentrations were also associated with the frequency of exhaustion, weakness and slowness. The corresponding odds ratios (95% confidence interval) for cadmium were, respectively, 0.97 (0.68–1.39) and 1.55 (1.03–2.32), but this association did not hold after excluding participants with reduced glomerular filtration rate: 0.70 (0.43–1.14) and 1.09 (0.56–2.11), respectively. Conclusions: In the US older adult population, blood lead but not urine cadmium concentrations showed a direct dose–response relationship with frailty. These findings support that lead exposure increases frailty in older adults. - Highlights: • No previous study has evaluated the association between lead, cadmium and frailty. • In NHANES III, blood lead levels showed a dose–response relationship with frailty. • Lead was also associated with higher frequency of exhaustion, weakness and slowness. • For cadmium, the results did not support an overall association with frailty.

54 ENVIRONMENTAL SCIENCES↗

DOE OSTI2017

Lead exposure is related to hypercortisolemic profiles and allostatic load in Brazilian older adults

Lead levels (Pb) have been linked to both hyper- and hypo-reactivity of hypothalamic-pituitary-adrenal axis (HPA) axis to acute stress in animals and humans. Similarly, allostatic load (AL), the ‘wear and tear’ of chronic stress, is associated with inadequate HPA axis activity. We examined whether Pb levels would be associated with altered diurnal cortisol profile, as a primary mediator of AL, during aging. Pb levels were measured from blood samples (BPb) of 126 Brazilian individuals (105 women), between 50 and 82 years old. Six neuroendocrine, metabolic, and anthropometric biomarkers were analyzed and values were transformed into an AL index using clinical reference cut-offs. Salivary samples were collected at home over 2 days at awakening, 30-min after waking, afternoon, and evening periods to determine cortisol levels. A multiple linear regression model showed a positive association between BPb as the independent continuous variable and cortisol awakening response (R{sup 2}=0.128; B=0.791; p=0.005) and overall cortisol concentration (R{sup 2}=0.266; B=0.889; p<0.001) as the outcomes. Repeated measures ANOVA showed that individuals with high BPb levels showed higher cortisol at 30 min after awakening (p=0.003), and in the afternoon (p=0.002) than those with low BPb values. Regarding AL, regression model showed that BPb was positively associated with AL index (R{sup 2}=0.100; B=0.204; p=0.032). Correlation analyzes with individual biomarkers showed that BPb was positively correlated with HDL cholesterol (p=0.02) and negatively correlated with DHEA-S (p=0.049). These findings suggest that Pb exposure, even at levels below the reference blood lead level for adults recommended by the National Institute for Occupational Safety and Health and by the Center for Disease Control and Prevention, may contribute to AL and dysregulated cortisol functioning in older adults. Considering these findings were based on cross-sectional data future research is needed to confirm our exploratory results. - Highlights: • Lead exposure is associated with several negative health outcomes. • Allostatic load (AL), the wear and tear of chronic stress, may be affected by lead exposure. • Lead concentration was associated with high cortisol levels and high allostatic load. • Even at very low levels of exposure, lead was associated with chronic stress mediators.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

Irradiation of rainbow trout at early life stages results in a proteomic legacy in adult gills. Part A; proteomic responses in the irradiated fish and in non-irradiated bystander fish

Highlights: • The effects of early life irradiation on the trout gill proteome was investigated. • The bystander effect proteomic responses in non-irradiated fish were investigated. • Proteomic responses of embryonic irradiation were anti-tumorigenic or anti-oxidant. • Proteomic responses of larval or first feeder irradiation were “dual function”. • Bystander effect proteomic responses were anti-tumorigenic or protective. Exposure to a single 0.5 Gy X-ray dose of eggs at 48 h after fertilisation (48 h egg), eyed eggs, yolk sac larvae (YSL) and first feeders induces a legacy effect in adult rainbow trout. This includes the transmission of a bystander effect to non-irradiated adult trout which had swam with the irradiated fish. The aim of this study was to investigate this legacy by analysing the gill proteome of these irradiated and bystander fish. Irradiation at all of the early life stages resulted in changes to proteins which play a key role in development but are also known to be anti-tumorigenic and anti-oxidant: upregulation of haemoglobin subunit beta (48 h egg), haemoglobin, serum albumin 1 precursor (eyed eggs), clathrin heavy chain 1 isoform X10 (eyed eggs and first feeders), and actin-related protein 2/3 complex subunit 4 (first feeders), downregulation of pyruvate dehydrogenase, histone 1 (48 h egg), triosephosphate isomerase (TPI), collagen alpha-1(1) chain like proteins (YSL), pyruvate kinase PKM-like protein (YSL and first feeders), ubiquitin-40S ribosomal proteins S27 and eukaryotic translation initiation factor 4 A isoform 1B (first feeders). However irradiation of YSL and first feeders (post hatching early life stages) also induced proteomic changes which have a complex relationship with tumorigenesis or cancer progression; downregulation of alpha-1-antiprotease-like protein precursor, vigilin isoform X2 and nucleoside diphosphate kinase (YSL) and upregulation of hyperosmotic glycine rich protein (first feeders). In bystander fish some proteomic changes were similar to those induced by irradiation: upregulation of haemoglobin subunit beta (48 h egg), haemoglobin (eyed eggs), actin-related protein 2/3 complex subunit 4, hyperosmotic glycine rich protein (first feeders), and downregulation of alpha-1-antiprotease-like protein, vigilin isoform X2, nucleoside diphosphate kinase (YSL), pyruvate kinase PKM-like protein and ubiquitin-40S ribosomal protein S27a-like (first feeders). Other proteomic changes were unique to bystander fish; downregulation of TPI, ubiquitin-40S ribosomal protein S2 (eyed egg), cofilin-2, cold-inducible RNA-binding protein B-like isoform X3 (YSL) and superoxide dismutase (first feeder), and upregulation of haemoglobin subunit alpha, collagen 1a1 precursor, apolipoprotein A-1-1 and A-1–2 precursor (first feeders). These bystander effect proteomic changes have been shown to be overwhelmingly anti-tumorigenic or protective of the fish gill.

63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTAN↗

DOE OSTI2018

Alzheimer's disease and alpha-synuclein pathology in the olfactory bulbs of infants, children, teens and adults ≤ 40 years in Metropolitan Mexico City. APOE4 carriers at higher risk of suicide accelerate their olfactory bulb pathology

Highlights: • Air pollution targets olfactory bulbs in young city dwellers. • Olfactory bulb hyperphosphorylated tau and Lewy neurites are present in Mexico City toddlers. • APOE4 carriers accelerate their OB pathology and have 4.7 times higher suicide odds v APOE3. • Olfactory testing may aid in identifying young persons at high risk for neurodegenerative disease. • Early neuroprotective interventions in PM{sub 2.5} and CDNP's exposed individuals ≤ 20 years are critical. There is growing evidence that air pollution is a risk factor for a number of neurodegenerative diseases, most notably Alzheimer's (AD) and Parkinson's (PD). It is generally assumed that the pathology of these diseases arises only later in life and commonly begins within olfactory eloquent pathways prior to the onset of the classical clinical symptoms. The present study demonstrates that chronic exposure to high levels of air pollution results in AD- and PD-related pathology within the olfactory bulbs of children and relatively young adults ages 11 months to 40 years. The olfactory bulbs (OBs) of 179 residents of highly polluted Metropolitan Mexico City (MMC) were evaluated for AD- and alpha-synuclein-related pathology. Even in toddlers, hyperphosphorylated tau (hTau) and Lewy neurites (LN) were identified in the OBs. By the second decade, 84% of the bulbs exhibited hTau (48/57), 68% LNs and vascular amyloid (39/57) and 36% (21/57) diffuse amyloid plaques. OB active endothelial phagocytosis of red blood cell fragments containing combustion-derived nanoparticles (CDNPs) and the neurovascular unit damage were associated with myelinated and unmyelinated axonal damage. OB hTau neurites were associated mostly with pretangle stages 1a and 1b in subjects ≤ 20 years of age, strongly suggesting olfactory deficits could potentially be an early guide of AD pretangle subcortical and cortical hTau. APOE4 versus APOE3 carriers were 6–13 times more likely to exhibit OB vascular amyloid, neuronal amyloid accumulation, alpha-synuclein aggregates, hTau neurofibrillary tangles, and neurites. Remarkably, APOE4 carriers were 4.57 times more likely than non-carriers to die by suicide. The present findings, along with previous data that over a third of clinically healthy MMC teens and young adults exhibit low scores on an odor identification test, support the concept that olfactory testing may aid in identifying young people at high risk for neurodegenerative diseases. Moreover, results strongly support early neuroprotective interventions in fine particulate matter (PM{sub 2.5}) and CDNP's exposed individuals ≤ 20 years of age, and the critical need for air pollution control.

54 ENVIRONMENTAL SCIENCES↗

DOE OSTI2022

Optimizing quantification of MK6240 tau PET in unimpaired older adults

Accurate measurement of Alzheimer's disease (AD) pathology in older adults without significant clinical impairment is critical to assessing intervention strategies aimed at slowing AD-related cognitive decline. The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (POINTER) is a 2-year randomized controlled trial to evaluate the effect of multicomponent risk reduction strategies in older adults (60-79 years) who are cognitively unimpaired but at increased risk for cognitive decline/dementia due to factors such as cardiovascular disease and family history. The POINTER Imaging ancillary study is collecting tau-PET ([ 18 F]MK6240), beta-amyloid (Aβ)-PET ([ 18 F]florbetaben [FBB]) and MRI data to evaluate neuroimaging biomarkers of AD and cerebrovascular pathophysiology in this at-risk sample. Here 481 participants (70.0±5.0; 66% F) with baseline MK6240, FBB and structural MRI scans were included. PET scans were coregistered to the structural MRI which was used to create FreeSurfer-defined reference regions and target regions of interest (ROIs). We also created off-target signal (OTS) ROIs to examine the magnitude and distribution of MK6240 OTS across the brain as well as relationships between OTS and age, sex, and race. OTS was unimodally distributed, highly correlated across OTS ROIs and related to younger age and sex but not race. Aiming to identify an optimal processing approach for MK6240 that would reduce the influence of OTS, we compared our previously validated MRI-guided standard PET processing and 6 alternative approaches. The alternate approaches included combinations of reference region erosion and meningeal OTS masking before spatial smoothing as well as partial volume correction. To compare processing approaches we examined relationships between target ROIs (entorhinal cortex (ERC), hippocampus or a temporal meta-ROI (MetaROI)) SUVR and age, sex, race, Aβ and a general cognitive status measure, the Modified Telephone Interview for Cognitive Status (TICSm). Overall, the processing approaches performed similarly, and none showed a meaningful improvement over standard processing. Across processing approaches we observed previously reported relationships with MK6240 target ROIs including positive associations with age, an Aβ+> Aβ- effect and negative associations with cognition. In sum, we demonstrated that different methods for minimizing effects of OTS, which is highly correlated across the brain within subject, produced no substantive change in our performance metrics. This is likely because OTS contaminates both reference and target regions and this contamination largely cancels out in SUVR data. Caution should be used when efforts to reduce OTS focus on target or reference regions in isolation as this may exacerbate OTS contamination in SUVR data.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

Sex-specific patterns and deregulation of endocrine pathways in the gene expression profiles of Bangladeshi adults exposed to arsenic contaminated drinking water

Arsenic contamination of drinking water occurs globally and is associated with numerous diseases including skin, lung and bladder cancers, and cardiovascular disease. Recent research indicates that arsenic may be an endocrine disruptor. This study was conducted to evaluate the nature of gene expression changes among males and females exposed to arsenic contaminated water in Bangladesh at high and low doses. Twenty-nine (55% male) Bangladeshi adults with water arsenic exposure ranging from 50 to 1000 μg/L were selected from the Folic Acid Creatinine Trial. RNA was extracted from peripheral blood mononuclear cells for gene expression profiling using Affymetrix 1.0 ST arrays. Differentially expressed genes were assessed between high and low exposure groups for males and females separately and findings were validated using quantitative real-time PCR. There were 534 and 645 differentially expressed genes (p < 0.05) in the peripheral blood mononuclear cells of males and females, respectively, when high and low water arsenic exposure groups were compared. Only 43 genes overlapped between the two sexes, with 29 changing in opposite directions. Despite the difference in gene sets both males and females exhibited common biological changes including deregulation of 17β-hydroxysteroid dehydrogenase enzymes, deregulation of genes downstream of Sp1 (specificity protein 1) transcription factor, and prediction of estrogen receptor alpha as a key hub in cardiovascular networks. Arsenic-exposed adults exhibit sex-specific gene expression profiles that implicate involvement of the endocrine system. Due to arsenic's possible role as an endocrine disruptor, exposure thresholds for arsenic may require different parameters for males and females. - Highlights: • Males and females exhibit unique gene expression changes in response to arsenic. • Only 23 genes are common among the differentially expressed genes for the sexes. • Male and female gene lists exhibit common biological implications. • Both sexes exhibit deregulation of cardiovascular and endocrine pathways.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

Exposure to bisphenol A in young adult mice does not alter ovulation but does alter the fertilization ability of oocytes

Follicle growth culminates in ovulation, which allows for the expulsion of fertilizable oocytes and the formation of corpora lutea. Bisphenol A (BPA) is present in many consumer products, and it has been suggested that BPA impairs ovulation; however, the underlying mechanisms are unknown. Therefore, this study first evaluated whether BPA alters ovulation by affecting folliculogenesis, the number of corpora lutea or eggs shed to the oviduct, ovarian gonadotropin responsiveness, hormone levels, and estrous cyclicity. Because it has been suggested (but not directly confirmed) that BPA exerts toxic effects on the fertilization ability of oocytes, a second aim was to evaluate whether BPA impacts the oocyte fertilization rate using an in vitro fertilization assay and mating. The possible effects on early zygote development were also examined. Young adult female C57BL/6J mice (39 days old) were orally dosed with corn oil (vehicle) or 50 μg/kg bw/day BPA for a period encompassing the first three reproductive cycles (12–15 days). BPA exposure did not alter any parameters related to ovulation. Moreover, BPA exposure reduced the percentage of fertilized oocytes after either in vitro fertilization or mating, but it did not alter the zygotic stages. The data indicate that exposure to the reference dose of BPA does not impact ovulation but that it does influence the oocyte quality in terms of its fertilization ability. - Highlights: • Bisphenol A targets the fertilization ability of oocytes. • Bisphenol A does not alter ovulation. • Young adult females may be susceptible to the effects of bisphenol A on fertilization.

60 APPLIED LIFE SCIENCES↗