Metabolism disrupted by night-shift sleep patterns

According to an NIEHS-funded study, being awake at night and asleep during the day — for example, night-shift workers — may be linked to disruptions in certain metabolites and pathways without affecting the brain’s master clock. The research may help explain why night-shift sleep patterns have been linked to such metabolic disorders as obesity and diabetes.

Using a laboratory-based sleep study, researchers examined differences between night-shift and day-shift sleep patterns of ten men and four women, ages 22 to 34 years. The research team found only small differences between day-shift and night-shift patterns for the hormones melatonin and cortisol, which are traditional markers of the body’s circadian clock. Of the 135 metabolites measured in blood, 65 of them had a significant daily rhythm. Of those, 24 showed a 12-hour shift in rhythm for the night-shift pattern after only three days.

Citation: Skene DJ, Skornyakov E, Chowdhury NR, Gajula RP, Middleton B, Satterfield BC, Porter KI, Van Dongen HPA, Gaddameedhi S.. 2018. Separation of circadian- and behavior-driven metabolite rhythms in humans provides a window on peripheral oscillators and metabolism. Proc Natl Acad Sci U S A 115(30):7825–7830. (Synopsis(https://factor.niehs.nih.gov/2018/9/papers/dert/#a2))

Legionnaires’ disease linked to Flint drinking water change

NIEHS grantees and colleagues found that an estimated 80 percent of Legionnaires’ disease cases that occurred during an outbreak in Genesee County, Michigan, could be attributed to the city of Flint’s drinking water supply being changed to the Flint River.

The researchers conducted a detailed statistical analysis of data on Legionnaires’ cases in the Michigan counties of Genesee, Wayne, and Oakland during 2011-2016. They found that the risk of a Flint resident having Legionnaires’ disease increased as the amount of free chlorine in their water decreased. The analysis also suggested that the 0.2 or 0.5 parts per million chlorine residual levels recommended by regulatory agencies might not be sufficient to protect communities from Legionella pneumophila exposure when water quality conditions support strong growth of the bacteria, which was the case in Flint during and immediately after the water change.

Citation: Zahran S, McElmurry SP, Kilgore PE, Mushinski D, Press J, Love NG, Sadler RC, Swanson MS. 2018. Assessment of the Legionnaires' disease outbreak in Flint, Michigan. Proc Natl Acad Sci U S A 115(8):E1730–E1739. (Synopsis(https://factor.niehs.nih.gov/2018/4/papers/dert/#a4))

RNA binding proteins and Alzheimer’s disease

Results from a mouse study, partly funded by NIEHS, showed that RNA-binding proteins likely play a key role in the development of Alzheimer’s disease (AD). The new findings revealed potential new therapeutic targets for the disease.

The brains of people with AD exhibit neurofibrillary tangles, or abnormal accumulations of the protein tau. Using cultured cells, the researchers showed that reducing levels of an RNA-binding protein called T-cell intracellular antigen 1 (TIA1) led to decreased tau accumulation.

The researchers studied mice that accumulated tau in the brain, which modeled AD. They found that reducing TIA1 decreased the amount of small tau clumps and increased the proportion of large tau clumps that generated neurofibrillary tangles and were less toxic. The study determined that TIA1 is important in mediating tau toxicity and suggests that RNA-binding proteins direct the pathway of tau aggregation and the neurodegeneration that follows.

Citation: Apicco DJ, Ash PEA, Maziuk B, LeBlang C, Medalla M, Al Abdullatif A, Ferragud A, Botelho E, Ballance HI, Dhawan U, Boudeau S, Cruz AL, Kashy D, Wong A, Goldberg LR, Yazdani N, Zhang C, Ung CY, Tripodis Y, Kanaan NM, Ikezu T, Cottone P, Leszyk J, Li H, Luebke J, Bryant CD, Wolozin B. 2018. Reducing the RNA binding protein TIA1 protects against tau-mediated neurodegeneration in vivo. Nat Neurosci 21(1):72–80. (Synopsis(https://factor.niehs.nih.gov/2018/2/papers/dert/#a3))

How particulate matter aggravates COPD

NIEHS grantees have uncovered the key molecular pathway involved in chronic obstructive pulmonary disease (COPD) induced by air pollution exposure. Although cigarette smoke is the most common irritant that causes COPD, at least one-fourth of individuals with COPD are nonsmokers, and thus, could have COPD linked to air pollution.

In the new study, the researchers investigated gene expression changes in mouse models with lesions similar to those induced by air pollution and in human bronchial epithelial cells after exposure to diesel exhaust particles, which are a major source of particulate matter (PM) air pollution. They found that diesel exhaust particles reduced gene expression for mitochondrial complexes I and V, and induced COPD-like symptoms in the mice. Treatment with taurine and 3-methyladenine completely restored mitochondrial gene expression levels and protected both the cells and animals from PM-induced COPD.

Citation: Li X, Yang H, Sun H, Lu R, Zhang C, Gao N, Meng Q, Wu S, Wang S, Aschner M, Wu J, Tang B, Gu A, Kay SA, Chen R. 2017. Taurine ameliorates particulate matter-induced emphysema by switching on mitochondrial NADH dehydrogenase genes. Proc Natl Acad Sci U S A 114(45):E9655–E9664. (Synopsis(https://factor.niehs.nih.gov/2018/1/papers/dert/#a4))

Possible explanation for male and female cardiovascular differences

NIEHS grantees discovered that estrogen can block the function of soluble epoxide hydrolase (sEH), an enzyme in cells that degrades chemically stable fatty acid metabolites. Because inhibition of sEH can be cardioprotective, this finding may help explain why women generally have a lower incidence of cardiovascular disease than men.

Using mice and human cells, the researchers showed that estrogen is responsible for DNA methylation of the gene Ephx2, which blocks the gene’s ability to promote sEH expression. Inhibition of sEH can raise levels of epoxyeicosatrienoic acids (EETs), which are omega-6 fatty acid metabolites that are generally degraded by sEH. Because EETs are cardioprotective and can lower blood pressure, increases in EETs caused by estrogen suppression of sEH can help protect against heart disease. The finding also highlights the potential for using sEH inhibitors to prevent negative cardiovascular outcomes that may result from estrogen deficiency.

Citation: Yang YM, Sun D, Kandhi S, Froogh G, Zhuge J, Huang W, Hammock BD, Huang A . 2018. Estrogen-dependent epigenetic regulation of soluble epoxide hydrolase via DNA methylation. Proc Natl Acad Sci U S A 115(3):613–618. (Synopsis(https://factor.niehs.nih.gov/2018/3/papers/dert/#a3))

PFAS exposure linked to body weight regulation

A study by NIEHS grantees suggested that exposure to perfluoroalkyl substances (PFASs) might make it harder to keep weight off after dieting. The authors used data from the two-year Preventing Overweight Using Novel Dietary Strategies Lost, a clinical trial in which overweight and obese individuals followed controlled weight reduction diets that restricted daily caloric intake. Weight loss generally occurred in the first 6 months, followed by 18 months of gradual weight regain.

Researchers measured five specific PFASs in participants’ blood and observed that the higher the blood levels of PFASs, the more weight participants gained back after the initial period of weight loss. Higher blood levels of these PFASs also correlated with lower resting metabolic rates during the weight regain period, which suggested that certain PFAS chemicals might contribute to weight gain by lowering the body’s resting metabolic rate.

Citation: Liu G, Dhana K, Furtado JD, Rood J, Zong G, Liang L, Qi L, Bray GA, DeJonge L, Coull B, Grandjean P, Sun Q. 2018. Perfluoroalkyl substances and changes in body weight and resting metabolic rate in response to weight-loss diets: a prospective study. PLoS Med 15(2):e1002502. (Synopsis(https://factor.niehs.nih.gov/2018/4/papers/dert/#a2))

New tumor-promoting pathway for liver cancer discovered

NIEHS grantees showed that chronic liver inflammation can promote cancer by suppressing one of the body’s natural mechanisms to fight cancer development. This new tumor-promoting pathway could lead to novel liver cancer treatments.

The researchers studied a new mouse model of liver cancer that more closely mimics the way human liver cancer develops. In these mice, tumors developed as a natural consequence of nonalcoholic steatohepatitis (NASH), a chronic metabolic disorder that causes liver damage, fibrosis, and cell mutations.

The researchers found that mutations associated with NASH provoked cytotoxic T cells to recognize and attack newly emerging cancer cells. However, chronic liver inflammation led to the accumulation of another type of immune cell, called immunosuppressive lymphocytes. The experiments showed that immunosuppressive lymphocytes used a molecule known as PD-L1 to interfere with cytotoxic T cells, which led to liver tumors in the mice with chronic inflammation.

Citation: Shalapour S, Lin XJ, Bastian IN, Brain J, Burt AD, Aksenov AA, Vrbanac AF, Li W, Perkins A, Matsutani T, Zhong Z, Dhar D, Navas-Molina JA, Xu J, Loomba R, Downes M, Yu RT, Evans RM, Dorrestein PC, Knight R, Benner C, Anstee QM, Karin M. 2017. Inflammation-induced IgA plus cells dismantle anti-liver cancer immunity. Nature 551(7680):340–345. (Synopsis(https://factor.niehs.nih.gov/2018/1/papers/dert/#a2)) (Story)

Computational tool predicts chemical toxicity

NIEHS grantees and colleagues developed a computational tool that uses the properties of a chemical to predict its toxicity. They determined that the tool can predict a toxicity value with an error of less than a factor of 10, making it useful for quickly assessing relative risks of chemicals for which traditional toxicity data or human health assessments are unavailable.

Using a comprehensive database of chemicals with existing regulatory toxicity values from U.S. federal and state agencies, the researchers developed quantitative structure-activity relationship (QSAR) models. The authors compared their QSAR model predictions to those based on high-throughput screening (HTS) assays. HTS assays rapidly measure the potential toxicity of large numbers of chemicals by exposing cells to chemicals and assessing cellular changes. The researchers found that the QSAR model predictions were more accurate and more precise than those based on HTS assays.

Citation: Wignall JA, Muratov E, Sedykh A, Guyton KZ, Tropsha A, Rusyn I, Chiu WA. 2018. Conditional toxicity value (CTV) predictor: an in silico approach for generating quantitative risk estimates for chemicals. Environ Health Perspect 126(5):057008. (Synopsis(https://factor.niehs.nih.gov/2018/8/papers/dert/#a3))

Sex-specific weight differences linked to pesticide exposure

Exposure to pesticides before birth have different effects on body weight and body composition in boys and girls, according to an NIEHS-funded study. Maternal DDT exposure was associated with higher weight in girls, and maternal pyrethroid exposure was linked to lower weight in boys.

The researchers looked at markers of exposure to the pesticides DDT, DDE, and pyrethroids in a group of mothers near the end of their pregnancies in Limpopo, South Africa. They measured the body mass index and weight of the children at 1 and 2 years of age.

Using sophisticated statistical pollutant models, the researchers looked at both individual and joint effects of the different pesticides. They noted differences in effects when looking at the mixture of insecticides compared with individual exposures. The authors emphasized the importance of the advanced statistical methods used to examine the health effects of chemical mixtures.

Citation: Coker E, Chevrier J, Rauch S, Bradman A, Obida M, Crause M, Bornman R, Eskenazi B . 2018. Association between prenatal exposure to multiple insecticides and child body weight and body composition in the VHEMBE South African birth cohort. Environ Int 113:122–132. (Synopsis(https://factor.niehs.nih.gov/2018/5/papers/dert/#a1))

Exosomes — missing link in asbestos-related biological effects

NIEHS grantees discovered that cells exposed to asbestos excrete exosomes with altered protein signatures, and these exosomes can alter cancer-related genes in mesothelial cells. Exosomes, which are small membrane-bound structures secreted by cells, have roles in cellular waste disposal, and in normal physiology and disease.

The researchers examined the effects of asbestos exposure in lung epithelial cells and macrophages, two types of cells that are initially exposed to inhaled asbestos fibers. They compared exposed and unexposed cells by examining the protein levels inside the exosomes that the cells released. They observed significantly different protein signatures in the exosomes from the asbestos-exposed cells. They then added the exosomes from asbestos-exposed cells to healthy human mesothelial cells and measured dramatic changes in several cancer-related genes in the cells. According to the authors, the genetic alterations may explain how asbestos exposure may lead to cancer.

Citation: Munson P, Lam YW, Dragon J, MacPherson M, Shukla A. 2018. Exosomes from asbestos-exposed cells modulate gene expression in mesothelial cells. FASEB J 32(8):4328–4342. (Synopsis(https://factor.niehs.nih.gov/2018/5/papers/dert/#a3))

Diet and the microbiome lead to cancer-related changes

Using a mouse model of diet-induced obesity, NIEHS scientists found that the combination of diet and the microbiome can affect gene expression in the colonic epithelium. The findings, which suggest these changes may lead to obesity, obesity-related diseases, and colon cancer, provide important insight into the relationship between the microbiome and host disease risk.

Male and female mice were fed a high-fat diet (HFD), or a low-fat control diet for 20 weeks. After sequencing 16S rDNA from fecal samples, the scientists found the HFD led to an altered microbiome before the development of obesity. The researchers also observed changes in histone methylation and acetylation at genomic loci associated with signaling pathways that were integral to the development of colon cancer. The research team found that transplantation of HFD-conditioned microbiota, combined with an obesogenic diet, recapitulated features of the long-term diet regimen.

Citation: Qin Y, Roberts JD, Grimm SA, Lih FB, Deterding LJ, Li R, Chrysovergis K, Wade PA. 2018. An obesity-associated gut microbiome reprograms the intestinal epigenome and leads to altered colonic gene expression. Genome Biol 19(1):7. (Synopsis(https://factor.niehs.nih.gov/2018/3/papers/dir/#a5))

NIEHS researchers develop new method to study brain diseases

NIEHS researchers developed a new tool called spectrally resolved fiber photometry that simultaneously measures the activities of two distinct neuronal populations that control movement in an animal model. These findings may help address Parkinson`s disease, a neurological disorder mainly characterized by tremors, slowness of movement, and impaired balance.

An animal’s ability to move is controlled by two groups of neurons in the brain’s basal ganglia, the direct pathway (D1) and the indirect pathway (D2). Scientists used a Cre-Lox vector-based strategy to target these striatal direct and indirect pathway neurons. They found when neural activity in D1 neurons is stronger than activity in D2 neurons, the animal does a start and go, meaning it starts and moves to another location. However, when D2 neuronal activity is stronger than D1 neurons, the mouse does a start and stop, meaning it initiates a movement, but stops immediately.

Citation: Meng C, Zhou J, Papaneri A, Peddada T, Xu K, Cui G. 2018. Spectrally resolved fiber photometry for multi-component analysis of brain circuits. Neuron 98(4):707–717.e4. (Synopsis(https://factor.niehs.nih.gov/2018/7/papers/dir/#a4)) (Story)

Recently discovered protein modification regulates glucose metabolism

Scientists at NIEHS and their collaborators showed that the enzyme p300 mediates lysine 2-hydroxyisobutyrylation (Khib), a recently discovered type of post-translational modification (PTM). The authors discovered that this PTM targets enzymes involved in glycolysis, a pathway that produces cellular energy from the breakdown of glucose. The findings reveal an important role of p300-mediated Khib in regulating cellular glucose metabolism.

The authors showed that, in addition to functioning as a writer for lysine acetylation (Kac), p300 can also act as a writer for Khib. PTMs, such as Khib and Kac, are known to regulate enzyme activity. Using a quantitative proteomics approach, the authors identified 149 potential p300-targeted Khib sites in HCT116 human cells. Interestingly, only 6 of these sites overlapped with p300-targeted Kac sites. These findings suggested that p300 exhibited a differential sequence preference between the two PTMs.

Citation: Huang H, Tang S, Ji M, Tang Z, Shimada M, Liu X, Qi S, Locasale JW, Roeder RG, Zhao Y, Li X. 2018. EP300-mediated lysine 2-hyroxyisobutyrylation regulates glycolysis. Mol Cell 70(4):663–678.e6. (Synopsis(https://factor.niehs.nih.gov/2018/7/papers/dir/#a2))

Study finds that bedroom allergens are widespread

Exposure to allergens in the home is ubiquitous, according to the nation’s largest indoor allergen study. Using data collected by the 2005-2006 National Health and Nutrition Examination Survey, NIEHS researchers found that allergen exposures in U.S. homes are highly variable and influenced by sociodemographic, regional, climate, and housing factors.

The research team investigated levels of eight common allergens in the bedrooms of nearly 7,000 homes. More than 90 percent of homes had three or more detectable allergens, and 73 percent had increased levels of at least one allergen. High allergen burden, meaning increased levels of exposure to multiple allergens, was most common in households with pets and pests, mobile homes, old homes and rental homes, and homes in rural areas. Researchers compared allergen exposure and sensitization patterns at the national level. Exposure patterns showed distinct differences by sex, race or ethnicity, and level of urbanization.

Citation: Salo PM, Wilkerson J, Rose KM, Cohn RD, Calatroni A, Mitchell HE, Sever ML, Gergen PJ, Thorne PS, Zeldin DC. 2018. Bedroom allergen exposures in U.S. households. J Allergy Clin Immunol 141(5):1870–1879.e14. (Synopsis(https://factor.niehs.nih.gov/2018/2/papers/dir/#a3)) (Story)

Molecular crosstalk in the ribosomal RNA processing complex

NIEHS scientists characterized Grc3, a protein that is essential in the processing of ribosomal RNA. Grc3 is a polynucleotide kinase (PNK), which is a class of enzymes that targets the 5-prime end of DNA and RNA substrates to transfer a phosphate from nucleoside triphosphates to the substrate. However, Grc3 is unable to carry out its kinase function on its own and needs a binding partner, the endoribonuclease Las1.

The authors generated a series of Grc3 variants to determine the requirements for kinase activity. Through a combination of in vitro and in vivo studies, the authors established the role of kinase motifs within Grc3 that can direct Las1 activity to carry out its nuclease function. The authors concluded that the complex shows metal and nucleotide selectivity similar to other members of the PNK family, but it exhibits critical differences in substrate selection.

Citation: Pillon MC, Sobhany M, Stanley RE. 2018. Characterization of the molecular crosstalk within the essential Grc3-Las1 pre-rRNA processing complex. RNA 24(5):721–738. (Synopsis(https://factor.niehs.nih.gov/2018/4/papers/dir/#a2))

DES reprograms development of mouse uterus

NIEHS researchers determined that the synthetic estrogen diethylstilbestrol (DES) can cause epigenetic changes and alter gene expression in the developing mouse uterus. The findings provide a crucial mechanism for the detrimental effects of estrogenic endocrine disruptors on development of the female reproductive system.

DES, once prescribed clinically to treat pregnancy complications, induces abnormal uterine structure and function, and increases cancer risk. The authors hypothesized that developmental exposure to DES affects the epigenome of the reproductive tract and results in permanently altered gene expression that contributes to poor reproductive health outcomes, including cancer.

The researchers exposed neonatal female mice to DES and analyzed the histone modifications of the uterine epigenome. They found that genes that were changed by DES had increased signals of the histone mark H3K27ac at their gene regulatory regions, including both the promoters and the enhancers.

Citation: Jefferson WN, Kinyamu HK, Wang T, Miranda AX, Padilla-Banks E, Suen AA, Williams CJ . 2018. Widespread enhancer activation via ERalpha mediates estrogen response in vivo during uterine development. Nucleic Acids Res 46(11):5487–5503. (Synopsis(https://factor.niehs.nih.gov/2018/6/papers/dir/#a3))

Multiethnic study reveals new genetic variants for lung function

Using meta-analysis of data from studies around the world, NIEHS researchers and their collaborators identified new genetic variants that are associated with lung function and risk of pulmonary disorders. By using integrative genomic tools and a large multiethnic population, the research expanded current information about genes related to respiratory health and provided insights into potential drug targets for lung diseases.

Both environmental and genetic factors influence pulmonary function traits (PFTs) that assess the physiological state of the lungs and are used clinically to diagnose and monitor lung diseases. Previous genome-wide association studies discovered nearly 100 PFT-associated DNA variants, mostly among people with European ancestry. This study gathered information from a much larger and diverse population of individuals from European, African, Asian, and Hispanic origins. The team reported more than 50 new variants associated with PFTs.

Citation: Wyss AB, Sofer T, Lee MK, Terzikhan N, Nguyen JN, Lahousse L, Latourelle JC, Smith AV, Bartz TM, Feitosa MF, Gao W, Ahluwalia TS, Tang W, Oldmeadow C, Duan Q, de Jong K, Wojczynski MK, Wang XQ, Noordam R, Hartwig FP, Jackson VE, Wang T, M Obeidat M, Hobbs BD, Huan T, Gui H, Parker MM, Hu D, Mogil LS, Kichaev G, Jin J, Graff M, Harris TB, Kalhan R, Heckbert SR, Paternoster L, Burkart KM, Liu Y, Holliday EG, Wilson JG, Vonk JM, Sanders JL, Barr RG, de Mutsert R, Menezes AMB, Adams HHH, van den Berge M, Joehanes R, Levin AM, Liberto J, Launer LJ, Morrison AC, Sitlani CM, Celedon JC, Kritchevsky SB, Scott RJ, Christensen K, Rotter JI, Bonten TN, Wehrmeister FC, Bosse Y, Xiao S, Oh S, Franceschini N, Brody JA, Kaplan RC, Lohman K, McEvoy M, Province MA, Rosendaal FR, Taylor KD, Nickle DC, Williams LK, Burchard EG, Wheeler HE, Sin DD, Gudnason V, North KE, Fornage M, Psaty BM, Myers RH, O’Connor G, Hansen T, Laurie CC, Cassano PA, Sung J, Kim WJ, Attia JR, Lange L, Boezen HM, Thyagarajan B, Rich SS, Mook-Kanamori DO, Horta BL, Uitterlinden AG, Im HK, Cho MH, Brusselle GG, Gharib SA, Dupuis J, Manichaikul A, London SJ. 2018. Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function. Nat Commun 9(1):2976. (Synopsis(https://factor.niehs.nih.gov/2018/10/papers/dir/#a4))

The brain’s stress chemical has surprising effects

A subset of brain cells that release a fight-or-flight signaling chemical called norepinephrine unexpectedly reduces anxiety in mice, according to a study by NIEHS researchers. Norepinephrine is a stress chemical that triggers anxiety. However, according to the study, noradrenergic neurons that transiently express a gene called Hoxb1 early in development have an opposite action, mimicking the effect of antidepressants by promoting a better coping response to stress and decreasing anxiety-like behavior.

To induce stress, the researchers forced mice to swim and recorded the time spent floating immobile to measure behavioral despair. To assess anxiety, the researchers recorded how much time mice spent in a comfortable, dark compartment of a box versus an aversive, illuminated section. Genetically modified mice with hyperactive Hoxb1-noradrenergic neurons spent less time immobile than did normal mice in the swim test. Moreover, activation of Hoxb1-noradrenergic neurons increased the time mice spent in the illuminated portion of a box.

Citation: Chen YW, Das M, Oyarzabal EA, Cheng Q, Plummer NW, Smith KG, Jones GK, Malawsky D, Yakel JL, Shih YI, Jensen P . 2018. Genetic identification of a population of noradrenergic neurons implicated in attenuation of stress-related responses. Mol Psychiatry; doi: 10.1038/s41380-018-0245-8 [Online 13 September 2018]. (Synopsis(https://factor.niehs.nih.gov/2018/11/papers/dir/#a4)) (Story)

Tumor suppressor p53 has broad role in homeostasis

The cancer-fighting protein p53 plays a broader role in human biology than previously thought, according to a study by NIEHS researchers. Their unprecedented insights may lead to the discovery of novel therapeutic targets for cancer and other diseases.

Researchers applied a uniform, rigorous analysis workflow to a large number of previously obtained p53 data sets, as well as their own data in normal immune cells. The results tripled the number of known cistrome genes, or those directly targeted by p53, to a total of 943. Moreover, the researchers identified a core signature of 28 cistrome genes that are consistently activated by p53. The core signature could act as a biomarker to assess the effectiveness of chemotherapies. The study provides a new dimension to the role of p53 in human biology, beyond its traditional function as a guardian of the genome.

Citation: Nguyen TT, Grimm SA, Bushel PR, Li J, Li Y, Bennett BD, Lavender CA, Ward JM, Fargo DC, Anderson CW, Li L, Resnick MA, Menendez D. 2018. Revealing a human p53 universe. Nucleic Acids Res 46(16):8153–8167. (Synopsis(https://factor.niehs.nih.gov/2018/10/papers/dir/#a2)) (Story)

A novel biomarker for acute respiratory distress syndrome

NIEHS researchers and their collaborators identified cholestenoic acid (CA) as a novel biomarker for acute respiratory distress syndrome (ARDS), a life-threatening respiratory condition characterized by tissue damage and fluid buildup in the lungs. ARDS has a high mortality rate of 30-40 percent, and only a few lung biomarkers, or measurable substances in the body that indicate disease, have been validated.

CA is produced in the lungs by alveolar macrophages, and previous studies determined that plasma CA levels decrease after surgical removal of the lung. The researchers hypothesized that plasma CA levels would decrease as the severity of ARDS increased in patients. Team members measured plasma CA levels in ARDS patients who participated in a trial conducted by the National Heart, Lung, and Blood Institute. They found that patients with lower CA levels experienced increased 90-day mortality, decreased ventilator-free days, and decreased days without organ failure.

Citation: Madenspacher JH, Stapleton RD, Suratt BT, Dixon AE, Lih FB, Lowe JM, Mould KJ, Janssen WJ, Morrell ED, Wurfel MM, Garantziotis S, Tomer KB, Fessler MB. 2018. Cholestenoic acid is a prognostic biomarker in acute respiratory distress syndrome. J Allergy Clin Immunol; doi: 10.1016/j.jaci.2018.09.017 [Online 5 October 2018]. (Synopsis(https://factor.niehs.nih.gov/2018/12/papers/dir/#a3))

Researchers identify protein necessary for pregnancy

A team led by NIEHS researchers found that SOX17 protein may be necessary for successful pregnancy. SOX17 mediates the activity of progesterone, the hormone responsible for regulating embryo implantation in the uterus. It was also shown to affect leukemia inhibitory factor (LIF) and Indian hedgehog homolog (IHH) signaling, two proteins implicated in establishing pregnancy.

The scientists used two infertile mice models for the first experiment. One model lacked SOX17 in cells that contained progesterone receptors, whereas the other lacked SOX17 in the uterine epithelium, the part of the uterus that first encounters a fertilized egg. Expression of LIF was significantly reduced in both models. For the second experiment, the team removed the SOX17 binding region of IHH, which resulted in significantly lower IHH expression in mice that lacked the SOX17 binding region compared with those with the binding region.

Citation: Wang X, Li X, Wang T, Wu S-P, Jeong J-W, Kim TH, Young SL, Lessey BA, Lanz RB, Lydon JP, DeMayo FJ. 2018. SOX17 regulates uterine epithelial-stromal cross-talk acting via a distal enhancer upstream of Ihh. Nat Commun 9(1):4421. (Synopsis(https://factor.niehs.nih.gov/2018/12/papers/dir/#a2)) (Story)

BMI linked to breast cancer risk in premenopausal women

Young obese women have a decreased risk of developing breast cancer before menopause, according to NIEHS scientists and their collaborators. The authors pooled individual-level data from 758,592 premenopausal women, ages 18 through 54 years, from 19 prospective cohorts from around the world. They assessed the relationship between breast cancer and different categories of the body mass index (BMI) at different ages.

This data set allowed the researchers to analyze associations in a larger number of categories than previous studies. They found that women who were overweight or obese at 18 to 24 years old had a much lower risk of breast cancer compared with other women with lower weight. The observed inverse association persisted for BMIs at other age ranges up until menopause, although the strength of the association grew weaker as age increased. These results suggest that the mechanisms leading to breast cancer may differ before and after menopause.

Citation: Premenopausal Breast Cancer Collaborative Group, Schoemaker MJ, Nichols HB, Wright LB, Brook MN, Jones ME, O’Brien KM, Adami H-O, Balietto L, Bernstein L, Bertrand KA, Boutron-Ruault M-C, Braaten T, Chen Y, Connor AE, Dorronsoro M, Dossus L, Eliassen AH, Giles GG, Hankinson SE, Kaaks R, Key TJ, Kirsh VA, Kitahara CM, Koh W-P, Larsson SC, Linet MS, Ma H, Masala G, Merritt MA, Milne RL, Overvad K, Ozasa K, Palmer JR, Peeters PH, Riboli E, Rohan TE, Sadakane A, Sund M, Tamimi RM, Trichopoulou A, Ursin G, Vatten L, Visvanathan K, Weiderpass E, Willett WC, Wolk A, Yuan J-M, Zeleniuch-Jacquotte A, Sandler DP, Swerdlow AJ. 2018. Association of body mass index and age with subsequent breast cancer risk in premenopausal women. JAMA Oncol 4(11):e181771. (Synopsis(https://factor.niehs.nih.gov/2018/8/papers/dir/#a5)) (Story)

NTP-led team creates sentinel gene set for exposures studies

Researchers from NTP and NIEHS partnered with members of the Tox21 project and the bioinformatics company SciOme to determine a set of genes used to detect human responses to exposures or diseases. The authors created the S1500-plus list by applying mathematical analyses of publicly available data on nearly 78,000 samples to identify highly informative sentinel genes.

The genes in the group were first selected by their power to differentiate between control and exposed samples. They were ranked for their capacity to predict the levels of other genes. The scientists then optimized the selection for maximal representation of all major biological functions. Finally, the scientific community nominated additional genes. After the data- and knowledge-driven effort, 2,739 genes were included in the S1500-plus gene set. It allowed the authors to predict levels of unmeasured genes and biological functions with high confidence.

Citation: Mav D, Shah RR, Howard BE, Auerbach SS, Bushel PR, Collins JB, Gerhold DL, Judson RS, Karmaus AL, Maull EA, Mendrick DL, Merrick BA, Sipes NS, Svoboda D, Paules RS. 2018. A hybrid gene selection approach to create the S1500-plus targeted gene sets for use in high-throughput transcriptomics. PLoS One 13(2):e0191105. (Synopsis(https://factor.niehs.nih.gov/2018/4/papers/dir/#a1))

Novel platform for sequencing rat genome coding regions

NTP researchers have established a novel platform to conduct whole exome sequencing (WES) in the rat, an animal model widely used in toxicology and pharmacology research. The tool developed in this study and the resulting data will help scientists better understand the rat genome and improve human translational research and environmental hazard evaluation.

WES offers an efficient approach to detect disease-related DNA mutations by sequencing the protein-coding regions of the genome. Using an in silico probe design approach, the authors targeted a probe set that is highly specific and sensitive to the rat genome, improving the currently limited rat WES tools.

On the new platform, the performance of formalin-fixed, paraffin-embedded (FFPE) tissue, which is routinely available in clinical settings, was comparable to that of paired fresh frozen samples, the standard source for DNA sequencing. It confirmed the feasibility of using FFPE samples for WES.

Citation: Foley JF, Phadke DP, Hardy O, Hardy S, Miller V, Madan A, Howard K, Kruse K, Lord C, Ramaiahgari S, Solomon GG, Shah RR, Pandiri AR, Herbert RA, Sills RC, Alex Merrick B. 2018. Whole exome sequencing in the rat. BMC Genomics 19(1):487. (Synopsis(https://factor.niehs.nih.gov/2018/8/papers/dir/#a1))

NTP finds high exposure to RFR linked to cancer in male rats

The NTP released its final reports from studies of rats and mice exposed to high levels of radio frequency radiation (RFR) like that used in 2G and 3G cell phones. NTP found clear evidence that exposed male rats developed cancerous heart tumors and some evidence that exposed male rats developed tumors in the brain and adrenal glands.

For female rats, and male and female mice, the researchers saw equivocal, or uncertain, evidence of associations between exposure to RFR and cancer. The final reports represent the consensus of NTP and an external expert panel that reviewed the studies in March.

The researchers said the results cannot be directly extrapolated to humans, but can still provide important information about RFR, which was previously assumed by many to be safe. The animals received RFR across their whole bodies at levels and durations greater than what people typically experience. (Synopsis(https://factor.niehs.nih.gov/2018/12/papers/dir/#a1)) (Story)

Citation: National Toxicology Program. 2018. Toxicology and carcinogenesis studies in Hsd:Sprague Dawley SD rats exposed to whole-body radio frequency radiation at a frequency (900 MHz) and modulations (GSM and CDMA) used by cell phones. TR 595. Research Triangle Park, NC: National Toxicology Program.National Toxicology Program. 2018. Toxicology and carcinogenesis studies in B6C3F1/N mice exposed to whole-body radio frequency radiation at a frequency (1,900 MHz) and modulations (GSM and CDMA) used by cell phones. TR 596. Research Triangle Park, NC: National Toxicology Program.