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DOE OSTI2016

Stimulation of nuclear receptor REV-ERBs regulates tumor necrosis factor-induced expression of proinflammatory molecules in C6 astroglial cells

Under physiological conditions, astrocytes maintain homeostasis in the CNS. Following inflammation and injury to the CNS, however, activated astrocytes produce neurotoxic molecules such as cytokines and chemokines, amplifying the initial molecular-cellular events evoked by inflammation and injury. Nuclear receptors REV-ERBα and REV-ERBβ (REV-ERBs) are crucial in the regulation of inflammation- and metabolism-related gene transcription. The current study sought to elucidate a role of REV-ERBs in rat C6 astroglial cells on the expression of inflammatory molecules following stimulation with the neuroinflammatory cytokine tumor necrosis factor (TNF). Stimulation of C6 cells with TNF (10 ng/ml) significantly increased the mRNA expression of CCL2, interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), and matrix metalloprotease (MMP)-9, but not fibroblast growth factor-2 (FGF-2), cyclooxygenase-2 (COX-2) and MMP-2. Treatment with either REV-ERB agonists GSK4112 or SR9009 significantly blocked TNF-induced upregulation of CCL2 mRNA and MMP-9 mRNA, but not IL-6 mRNA and iNOS mRNA expression. Furthermore, treatment with RGFP966, a selective histone deacetylase 3 (HDAC3) inhibitor, potently reversed the inhibitory effects of GSK4112 on TNF-induced expression of MMP-9 mRNA, but not CCL2 mRNA. Expression of Rev-erbs mRNA in C6 astroglial cells, primary cultured rat cortical and spinal astrocytes was confirmed by reverse transcription polymerase chain reaction. Together, the findings demonstrate an anti-inflammatory effect, downregulating of MMP-9 and CCL2 transcription, of astroglial REV-ERBs activation through HDAC3-dependent and HDAC3-independent mechanisms. - Highlights: • Rev-erbα mRNA and Rev-erbβ mRNA are expressed in C6 astroglial cells. • TNF increases the expression of CCL2, IL-6, MMP-9 and iNOS mRNA. • REV-ERB activation inhibits CCL2 mRNA and MMP-9 mRNA expression. • HDAC3 activity is involved in the inhibitory effect of REV-ERB on MMP-9 induction.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

NSrp70 is significant for embryonic growth and development, being a crucial factor for gastrulation and mesoderm induction

NSrp70 (nuclear speckle-related protein 70), a recently discovered protein and it belongs to the serine/arginine (SR) rich related protein family. NSrp70 is recognized as an important splicing factor comprising RNA recognition motif (RRM) and arginine/serine (RS)-like regions at the N- and C-terminus respectively, along with two coiled coil domains at each terminus. However, other functions of NSrp70 remain unelucidated. In this study, we investigated the role of NSrp70 in Xenopus embryogenesis and found that its maternal expression plays a critical role in embryonic development. Knockdown of NSrp70 resulted in dramatic reduction in the length of developing tadpoles and mild to severe malformation in Xenopus embryos. In addition, knockdown of NSrp70 resulted in an extremely short axis by blocking gastrulation and convergent extension. Further, animal cap assays along with activin A treatment revealed that NSrp70 is an essential factor for dorsal mesoderm induction as knockdown of NSrp70 caused a dramatic down-regulation of dorsal mesoderm specific genes and its loss significantly shortened the elongation region of animal caps. In conclusion, NSrp70 is crucial for early embryonic development, influencing gastrulation and mesoderm induction. - Highlights: • NSrp70 is required for proper length and dorso-anterior structures. • NSrp70 is essential for gastrulation movement during embryogenesis. • NSrp70 is crucial component for dorsal mesoderm induction.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2017

Preventative effect of OMZ-SPT on lipopolysaccharide-induced acute lung injury and inflammation via nuclear factor-kappa B signaling in mice

Acute lung injury (ALI) is an early pathophysiologic change in acute respiratory distress syndrome and its management can be challenging. Omalizumab (Xolair™) is a recombinant DNA-derived, humanized antibody. OMZ-SPT is a polypeptide on the heavy chain of omalizumab monoclonal antibody. Here, we found that intramuscular administration of OMZ-SPT significantly improved survival and attenuated lung inflammation in female C57BL/6 mice suffering from lipopolysaccharide (LPS)-induced ALI. We also demonstrated that OMZ-SPT can inhibit expression of the inflammatory cytokines tumor necrosis factor-α, interleukin-1β and interleukin-6 by ELISA in mice suffering from LPS-induced ALI and a mouse macrophage line (RAW264.7 cells). In addition, we showed that OMZ-SPT inhibited LPS-induced activation of nuclear factor-kappa B (NF-κB) signaling and total expression of NF-κB by western blotting. These data suggest that OMZ-SPT could be a novel therapeutic choice for ALI. - Highlights: • OMZ-SPT is a polypeptide on the heavy chain of omalizumab monoclonal antibody. • Omalizumab (Xolair™) have anti-inflammatory effects. • OMZ-SPT can inhibit inflammatory responses and lung injury in LPS-induced ALI mice. • Protective effect of OMZ-SPT on ALI is due to inhibition of NF-κB signaling. • OMZ-SPT could be a novel therapeutic choice for ALI.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2017

NF-κB signaling and cell-fate decision induced by a fast-dissociating tumor necrosis factor mutant

Tumor necrosis factor (TNF) is a pluripotent inflammatory cytokine that can induce both the pro-survival nuclear factor kappa B (NF-κB) pathway and the pro-apoptotic caspase pathway. Selectively activating only one of the two pathways remains challenging. We used TNF mutants with different receptor binding kinetics to study their effects on NF-κB signaling dynamics and cell apoptosis. A TNF mutant, R1antTNF, which binds to TNFR1 with increased association and dissociation rates, induced NF-κB signaling with shorter response time and first peak duration. The short nuclear stay of NF-κB led to biased activation of downstream genes, favoring the fast response ones. At the same time, R1antTNF retains pro-apoptotic activity. At 10 ng/ml, R1antTNF selectively activated the pro-apoptotic pathway rather than the pro-survival NF-κB pathway. Our study provides a new example for the emerging evidence that ligand-receptor binding kinetics play a key role in the selective activation of downstream pathways, which deserves more attention in future drug discovery and disease studies. - Highlights: • Receptor-TNF and mutant binding kinetics changes lead to functional selectivity. • R1antTNF is a fast associating and fast dissociating TNF mutant. • R1antTNF produces shortened nuclear duration of NF-κB. • R1antTNF induces biased gene expression of early-response genes. • R1antTNF selectively activates apoptosis at low concentration.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

The splicing factor transformer2 (tra2) functions in the Drosophila fat body to regulate lipid storage

Highlights: • Transformer2 (tra2) is a splicing protein whose metabolic functions are unknown. • Tra2 functions in the Drosophila fat body to modulate triglyceride levels. • Decreasing tra2 in the fat body promotes starvation resistance. • Tra2 alters CPT1 splicing in the fly fat body. Excess nutrients are stored as triglycerides mainly in the adipose tissue of an animal and these triglycerides are located in structures called lipid droplets. Previous genome-wide RNAi screens in Drosophila cells identified splicing factors as playing a role in lipid droplet formation. Our lab has recently identified the SR protein, 9G8, as an important factor in fat storage as decreasing its levels results in augmented triglyceride storage in the fat body. Previous in vitro studies have implicated 9G8 in the regulation of splicing of the sex determination gene doublesex (dsx) by binding to transformer (tra) and transformer2 (tra2); however, any function of these sex determination proteins in regulating metabolism is unknown. In this study, we have uncovered a role of tra2 to regulate fat storage in vivo. Inducing tra2{sup dsRNA} in the adult fat body resulted in an increase in triglyceride levels but had no effect on glycogen storage. Consistent with the triglyceride phenotype, tra2 knockdown flies lived longer under starvation conditions. In addition, this increase in triglycerides is due to more fat storage per cell and not an increase in the number of fat cells. Interestingly, the splicing of CPT1, an enzyme involved in the breakdown of lipids, was altered in flies with decreased tra2. The less-catalytically active isoform of CPT1 accumulated in tra2{sup dsRNA} flies suggesting a decrease in lipid breakdown, which is consistent with the increased triglyceride levels observed in these flies. Together, these results suggest a link between mRNA splicing, sex determination and lipid metabolism and may provide insight into the mechanisms underlying tissue-specific splicing and nutrient storage.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

Folic acid prevents methotrexate-induced epithelial-mesenchymal transition via suppression of secreted factors from the human alveolar epithelial cell line A549

Highlights: • FA inhibited MTX-induced EMT-like phenotypical changes of A549 cells. • FA inhibited MTX-stimulated release of factors that can induce EMT in A549 cells. • FA inhibited EMT induced by the conditioned medium prepared after MTX treatment. Methotrexate (MTX) often induces serious lung diseases such as pulmonary fibrosis. Although MTX is known to be a folic acid (FA) antagonist, the effect of FA on MTX-induced lung injury remains unclear. Recent studies indicate that epithelial-mesenchymal transition (EMT) is involved in pulmonary fibrosis. Here, we aimed to clarify the effect of FA on MTX-induced EMT in human alveolar epithelial cell line A549 using conditioned medium (CM). CM was prepared from the supernatants of A549 cells treated with MTX in the absence (CMM) or presence (CMMF) of FA. FA suppressed EMT-like morphological changes and elevated mRNA/protein expression levels of α-smooth muscle actin induced by MTX in A549 cells. In addition, CMM induced EMT-like phenotypical changes, whereas CMMF had no effect on the phenotype of A549 cells, indicating that FA may suppress MTX-induced EMT via inhibiting the secretion of certain factors into the supernatant of the cells. Furthermore, FA also prevented CMM-induced EMT-like phenotypical changes in A549 cells. These findings indicate that FA may be a useful pharmaceutical for MTX-induced lung injury.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

Identification of cathepsin B as a novel target of hypoxia-inducible factor-1-alpha in HepG2 cells

Highlights: • Cathepsin B (CTSB) is a novel target gene of hypoxia-inducible factor-1-alpha (HIF-1α). • CTSB mRNA and protein levels can be up-regulated in a HIF-1α-dependent manner. • CTSB promoter activity can be elevated by the HIF-1α protein. • HIF-1α protein binds the CTSB promoter directly. Hypoxia-inducible factor-1-alpha (HIF-1α) activates the transcription of many genes that code for proteins involved in angiogenesis, glucose metabolism, cell proliferation/survival, and invasion/metastasis. However, the mechanisms between HIF-1 and its downstream target genes are still poorly understood. Our experimental results had shown that nuclear HIF-1α proteins were significantly induced after HepG2 cells treatment with 1% O{sub 2} for 6 h and reached the peak expression level in 24 h. Meanwhile, the results of RT-qPCR and Western-blotting showed that HIF-1α and cathepsin B (CTSB) expressions increased with a similar pattern in response to hypoxia in the HepG2 cells. Additionally, based on bioinformatics analysis, we identified a hypoxia response element in the CTSB promoter, indicating a possible association between HIF-1α and CTSB. Moreover, luciferase assay was performed to reflect the transcriptional activity mediated through the HIF-1α binding HRE within the CTSB promoter. Furthermore, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (CHIP) revealed a specific HIF-1α binding activity to the CTSB gene promoter. For the first time, we demonstrated that CTSB is a new HIF-1α-target gene. We believe these findings will contribute to the research and development of neoplasm-targeted therapies.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

A negative feedback loop between nuclear factor 90 (NF90) and an anti-oncogenic microRNA, miR-7

Highlights: • miR-7, an anti-oncogenic miRNA, represses NF90 at the mRNA level. • The coding region of the NF90 mRNA is directly targeted by miR-7. • A rise in NF90 is attributed to negative feedback between NF90 and miR-7 in tumors. Alterations in microRNAs (miRNAs) levels deeply correlate with tumorigenesis. However, the molecular mechanism for the regulation of the miRNA production in tumors is not fully understood. We previously reported that downregulation of miR-7, which is an anti-oncogenic miRNA, was caused by overexpression of the nuclear factor 90 (NF90)-nuclear factor 45 (NF45) complex through the binding of double-stranded (ds) RNA-binding proteins to primary miR-7, resulting in promotion of tumorigenesis (Higuchi et al 2016). During this study, we found that the level of NF90 protein was dramatically decreased by overexpression of miR-7. Interestingly, the miR-7-mediated reduction in NF90 family proteins was only observed in NF90 protein, but not in NF110 protein, which is a longer form of the NF90 gene. Luciferase reporter analysis indicated that the overexpression of miR-7 significantly repressed the luciferase activity in the coding region of NF90 mRNA harboring a predicted target sequence of miR-7. The luciferase activity of the reporter vector, which has a mutated miR-7 target site in the coding region, was the same in the control and miR-7 overexpressed cells. Furthermore, the translation of TARGET-tagged NF90 mRNA without the 3′UTR of the NF90 mRNA was inhibited by the overexpression of miR-7. These results imply that miR-7 suppresses NF90 at the protein level through the binding of miR-7 to the complementary site of the seed sequence in the coding region of the NF90 mRNA. We further confirmed increased endogenous NF90 protein levels in SK-N-SH cells transfected with antisense oligonucleotides targeting miR-7, indicating that miR-7-mediated translational repression of NF90 is a physiological event. Taken together with our previous findings (Higuchi et al 2016), it suggests that the level of NF90 is increased by a negative feedback loop between NF90 and miR-7 in tumor tissues under physiological conditions.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

Effect of growth differentiation factor-15 secreted by human umbilical cord blood-derived mesenchymal stem cells on amyloid beta levels in in vitro and in vivo models of Alzheimer's disease

Highlights: • Paracrine action of hUCB-MSCs enhances Aβ clearance through microglial modulation. • GDF-15 secreted from hUCB-MSCs promotes the decrease of Aβ levels via enhancing IDE expression in microglia. • TGFβRII is involved in GDF-15-enhanced IDE expression in microglia. Alzheimer's disease (AD), which is the most common progressive neurodegenerative disease, causes learning and memory impairment. The pathological progress of AD can derive from imbalanced homeostasis of amyloid beta (Aβ) in the brain. In such cases, microglia play important roles in regulating the brain Aβ levels. In the present study, we found that human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) can increase, through paracrine action, the ability of microglial cells to clear Aβ. In order to identify the associated paracrine factors, a secretome of hUCB-MSCs co-cultured with Aβ-treated BV2 microglial cells was analyzed using a human cytokine protein array. As a result, growth differentiation factor-15 (GDF-15) was identified as a predominant candidate, and its association with Aβ clearance by microglial cells was investigated in vitro and in a 5XFAD mouse model. When Aβ-treated BV2 cells were treated with exogenous recombinant GDF-15, the Aβ levels in the culture medium decreased. Moreover, GDF-15 injection in the brain parenchyma of 5XFAD mice also led to decrease in Aβ plaques. In contrast, co-culture of BV2 cells and hUCB-MSCs treated with GDF-15-specific siRNA did not influence the Aβ levels in the culture medium. To elucidate how these phenomena are related, we confirmed that GDF-15 specifically increases insulin-degrading enzyme (IDE) expression in microglial cells through TGFβ receptor type II (TGFβRII), both in vitro and in vivo. These findings suggest that hUCB-MSCs promote the Aβ clearance ability of microglial cells through regulation of GDF-15 secretion, thus elucidating a therapeutic mechanism for AD.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2014

The effect of retinal pigment epithelial cell patch size on growth factor expression

The spatial organization of retinal pigment epithelial (RPE) cells grown in culture was controlled using micropatterning techniques in order to examine the effect of patch size on cell health and differentiation. Understanding this effect is a critical step in the development of multiplexed high throughput fluidic assays and provides a model for replicating disease states associated with the deterioration of retinal tissue during age-related macular degeneration (AMD). Microcontact printing of fibronectin on polystyrene and glass substrates was used to promote cell attachment, forming RPE patches of controlled size and shape. These colonies mimic the effect of atrophy and loss-of-function that occurs in the retina during degenerative diseases such as AMD. After 72 hours of cell growth, levels of vascular endothelial growth factor (VEGF), an important biomarker of AMD, were measured. Cells were counted and morphological indicators of cell viability and tight junction formation were assessed via fluorescence microscopy. As a result, up to a twofold increase of VEGF expression per cell was measured as colony size decreased, suggesting that the local microenvironment of, and connections between, RPE cells influences growth factor expression leading to the initiation and progression of diseases such as AMD.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2021

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Suicide is a leading cause of death worldwide, and non-fatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium. The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via mtCOJO, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders and other known risk factors. Results: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with non-psychiatric traits remained largely unchanged. Conclusions: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2021

Understanding of the factors slowing down metakaolin reaction in limestone calcined clay cement (LC3) at late ages

Factors which could explain the slowing down of the metakaolin reaction in LC{sup 3} blends are investigated. Portlandite availability and the presence of aluminium ions in the pore solution are shown not to be limiting factors. Hydrates can only precipitate in solution filled pores. Internal relative humidity measurements indicate that at 28 days solution is present only in pores with radii below 13 nm. An enhancement of metakaolin reaction was obtained at late ages when the larger capillaries are filled with solution. The lower limit of the water filled pores was more difficult to analyse since there is a lack of precision in determining interfacial energies of hydrates and pore solution of the system. However, this study gives an indication of order of magnitude where the growth of hydrates could be slowed down.

36 MATERIALS SCIENCE↗

DOE OSTI2016

Lessons from the Crystal Structure of the S. aureus>/em> Surface Protein Clumping Factor A in Complex With Tefibazumab, an Inhibiting Monoclonal Antibody

The Staphylococcus aureus fibrinogen binding MSCRAMM (Microbial Surface Components Recognizing Adhesive Matrix Molecules), ClfA (clumping factor A) is an important virulence factor in staphylococcal infections and a component of several vaccines currently under clinical evaluation. The mouse monoclonal antibody aurexis (also called 12-9), and the humanized version tefibazumab are therapeutic monoclonal antibodies targeting ClfA that in combination with conventional antibiotics were effective in animal models but showed less impressive efficacy in a limited Phase II clinical trial. We here report the crystal structure and a biochemical characterization of the ClfA/tefibazumab (Fab) complex. The epitope for tefibazumab is located to the “top” of the N3 subdomain of ClfA and partially overlaps with a previously unidentified second binding site for fibrinogen. A high-affinity binding of ClfA to fibrinogen involves both an interaction at the N3 site and the previously identified docking of the C-terminal segment of the fibrinogen γ-chain in the N2N3 trench. Although tefibazumab binds ClfA with high affinity we observe a modest IC50 value for the inhibition of fibrinogen binding to the MSCRAMM. This observation, paired with a common natural occurring variant of ClfA that is not effectively recognized by the mAb, may partly explain the modest effect tefibazumab showed in the initial clinic trail. This information will provide guidance for the design of the next generation of therapeutic anti-staphylococcal mAbs targeting ClfA.

General & Internal Medicine↗

DOE OSTI2014

Uncovering the factors that can support and impede post-disaster EIA practice in developing countries: The case of Aceh Province, Indonesia

The close relationship between environmental degradation and the occurrence and severity of disaster events has in recent years raised the profile of environmental assessment (EA) in the disaster management field. EA has been identified as a potentially supportive tool in the global effort to reduce disaster risk. As a component of this, attention has been brought specifically to the importance of the application of EA in the aftermath of disaster events in order to help prevent recurrence and promote sustainability. At the same time, however, it has also been recognised that post-disaster environments may be unfavourable to such practices. Looking at the practice of environmental impact assessment (EIA), this paper reports on a study which sought to identify more specifically the factors which can both support and hinder such practice following disaster events in a developing country context. Analysing the situation in Aceh Province, Indonesia, after the impact of two tsunamigenic earthquakes in late 2004 and early 2005, it is concluded that if EIA is to have a central role in the post-disaster period, pre-disaster preparation could be a key. -- Highlights: • Close relationship between environmental degradation and occurrence/severity of disaster events has raised profile of EA. • EA as a potentially supportive tool in the global effort to reduce disaster risk • Application of EA in the aftermath of disaster events to help prevent recurrence and promote sustainability • The paper looks at factors which can both support and hinder EA following disaster events in a developing country context. • We analyse the situation in Aceh Province, Indonesia, after the impact of two tsunamigenic earthquakes in 2004 and 2005.

22 GENERAL STUDIES OF NUCLEAR REACTORS↗

DOE OSTI2014

Combined impact of lead, cadmium, polychlorinated biphenyls and non-chemical risk factors on blood pressure in NHANES

High blood pressure is associated with exposure to multiple chemical and non-chemical risk factors, but epidemiological analyses to date have not assessed the combined effects of both chemical and non-chemical stressors on human populations in the context of cumulative risk assessment. We developed a novel modeling approach to evaluate the combined impact of lead, cadmium, polychlorinated biphenyls (PCBs), and multiple non-chemical risk factors on four blood pressure measures using data for adults aged ≥20 years from the National Health and Nutrition Examination Survey (1999–2008). We developed predictive models for chemical and other stressors. Structural equation models were applied to account for complex associations among predictors of stressors as well as blood pressure. Models showed that blood lead, serum PCBs, and established non-chemical stressors were significantly associated with blood pressure. Lead was the chemical stressor most predictive of diastolic blood pressure and mean arterial pressure, while PCBs had a greater influence on systolic blood pressure and pulse pressure, and blood cadmium was not a significant predictor of blood pressure. The simultaneously fit exposure models explained 34%, 43% and 52% of the variance for lead, cadmium and PCBs, respectively. The structural equation models were developed using predictors available from public data streams (e.g., U.S. Census), which would allow the models to be applied to any U.S. population exposed to these multiple stressors in order to identify high risk subpopulations, direct intervention strategies, and inform public policy. - Highlights: • We evaluated joint impact of chemical and non-chemical stressors on blood pressure. • We built predictive models for lead, cadmium and polychlorinated biphenyls (PCBs). • Our approach allows joint evaluation of predictors from population-specific data. • Lead, PCBs and established non-chemical stressors were related to blood pressure. • Framework allows cumulative risk assessment in specific geographic settings.

54 ENVIRONMENTAL SCIENCES↗

DOE OSTI2017

Factors associated with serum thyroglobulin in a Ukrainian cohort exposed to iodine-131 from the accident at the Chernobyl Nuclear Plant

Background: Serum thyroglobulin (Tg) is associated with the presence of thyroid disease and has been proposed as a biomarker of iodine status. Few studies have examined factors related to serum Tg in populations environmentally exposed to ionizing radiation and living in regions with endemic mild-to-moderate iodine deficiency. Methods: We screened 10,430 individuals who were living in Ukraine and under 18 years of age at the time of the 1986 Chernobyl Nuclear Power Plant accident for thyroid disease from 2001 to 2003. We estimated the percent change (PC) in serum Tg associated with demographic factors, iodine-131 thyroid dose, and indicators of thyroid structure and function using linear regression. We also examined these relationships for individuals with and without indications of thyroid abnormality. Results: Mean and median serum Tg levels were higher among participants with abnormal thyroid structure/function. Percent change in serum Tg increased among females, smokers and with older age (p-values<0.001), and Tg increased with increasing thyroid volume, and serum thyrotropin (p-values for trend<0.001). We found no evidence of significant associations between iodine-131 thyroid dose and Tg. Serum Tg levels were inversely associated with iodized salt intake (PC=−7.90, 95% confidence interval: −12.08, −3.52), and over the range of urinary iodine concentration, the odds of having elevated serum Tg showed a U-shaped curve with elevated Tg at low and high urinary iodine concentrations. Conclusion: Serum Tg may be a useful indicator of population iodine status and a non-specific biomarker of structural and functional thyroid abnormalities in epidemiological studies. - Highlights: • We evaluated serum thyroglobulin (Tg) in 10,430 irradiated, mostly iodine deficient Ukrainians. • Tg levels were higher among subjects with abnormal thyroid structure/function. • Increased Tg was associated with increasing age, thyroid volume and thyrotropin levels. • The odds of elevated Tg showed a U-shaped curve over categories of dietary iodine status. • Serum Tg is a useful indicator of population iodine status and thyroid abnormalities.

54 ENVIRONMENTAL SCIENCES↗

DOE OSTI2018

Contribution of diet and other factors to the observed levels of selected perfluoroalkyl acids in serum among US children aged 3-11 years

Highlights: • Diet was the predominant factor in explaining variability associated with PFAAs. • Boys had higher adjusted geometric mean than girls for MPAH and NPFOS. • Exposure to ETS was associated with 12.6% increase in the levels of NPFOA. Data from National Health and Nutrition Examination Survey for 2013–2014 for children aged 3–11 years (N = 639) were analyzed to evaluate the contribution of diet and other factors in variability associated with the observed levels of seven perfluoroalkyl acids in serum, namely, 2(N-methyl-perfluorooctane sulfonamide) acetic acid (MPAH), perfluorodecanoic acid (PFDE), perfluorononanoic acid (PFNA), perflurorohexane sulfonic acid (PFHxS), linear isomer of PFOA (NPFOA), linear isomer of PFOS (NPFOS), and monomethyl isomer of PFOS (MPFOS). Diet accounted for a low of 18.6% of the total explained variance in the adjusted levels of NPFOA and a high of 72.3% for PFNA. Consumption of meat other than fish and poultry was associated with increased levels of NPFOS (β = 0.00035, p < 0.01) and MPFOS (β = 0.00027, p=0.02). However, consumption of fish was associated with decreased levels of PFDE (β = − 0.00058, p=0.01). Consumption of eggs was associated with higher levels of PFDE (β = 0.00105, p=0.04). Higher levels of PFHxS were associated with consumption of fruits and juices (β = 0.00019, p = 0.03). Exposure to environmental tobacco smoke in indoor environments other than home was associated with 12.6% increase in the levels of NPFOA. Boys had higher adjusted geometric mean (AGM) than girls for MPAH (0.88 vs. 0.70 ng/mL, p = 0.04) and NPFOS (2.73 vs. 2.27 ng/mL, p = 0.04). Non-Hispanic white had higher AGMs than Hispanics for MPAH (0.15 vs. 0.07, p < 0.01), for NPFOA (1.98 vs. 1.64 ng/mL, p < 0.01), and MPFOS (1.39 vs. 1.18 ng/mL, p = 0.03). Non-Hispanic white also had higher AGM than non-Hispanic Asians and others for PFHxS (0.99 vs. 0.63 ng/mL, p < 0.01) and NPFOA (1.98 vs. 1.53 ng/mL, p < 0.01).

54 ENVIRONMENTAL SCIENCES↗

DOE OSTI2018

Relationships between physical–geographical factors and soil degradation on agricultural land

Highlights: • Connection of soil degradation to seven physical-geographical variables was revealed. • New method of threshold data analysis was proposed. • Precise treshold values where soil degradation starts and ends were revealed. • Study area covered the entire area of Czech agricultural land – 13027 cadastres (78,866 km{sup 2}). It is a well-known fact that soil degradation is dramatically increasing and currently threatens agricultural soils all around the world. The objective of this study was to reveal the possible connection between soil degradation and seven physical-geographical factors - slope steepness, altitude, elevation differences, rainfall, temperature, soil texture and solar radiation – in the form of threshold values (if these exist), where soil degradation begins and ends. The analysis involved the whole area of the Czech Republic which consists of 13,027 cadasters (78,866 km{sup 2}). The greatest total degradation threat occurs in areas with slope steepness >7 degrees, average annual temperature 10.54, altitude >766 m a.s.l. Similarly, the results for water erosion, wind erosion, soil compaction, loss of organic matter, acidification and heavy metal contamination were processed. The results enable us to identify the relationships of different levels of threats which could consequently be used in various ways – for classification of threatened areas, for more effective implementation of anti-degradation measures, or purely for a better understanding of the role of physical geographical factors in soil degradation in the Czech Republic, and thus could increase the chances of reducing vulnerability to land degradation not only in the Czech Republic.

54 ENVIRONMENTAL SCIENCES↗