Papers of the Month
Intramural
By Nicholas Alagna, Sanya Mehta, Prashant Rai, Janelle Weaver, and Qing Xu
DNTP studies health effects of potentially toxic chemical from refineries
Research from the Division of the National Toxicology Program demonstrated differences across species in response to exposure to sulfolane, a potentially toxic compound used during industrial refining. Originally developed by Shell Oil Company in the 1950s, sulfolane has been detected in groundwater sources near refining sites. Currently, there are no federal regulatory limits for sulfolane levels in drinking water. Health effects of this chemical on humans have not been well-characterized, particularly after oral exposure.
Due to potentially large species differences, the researchers compared the effects of sulfolane on rats, mice, and guinea pigs after 28 days of oral exposure to a wide range of doses. Male rats appeared to be the most sensitive to the compound, showing evidence of kidney abnormalities, while guinea pigs appeared to be the least sensitive. Sulfolane induced lesions in different tissues across the three species. In addition, plasma levels were generally higher in rats and guinea pigs compared to mice, which corresponded to observed effects.
As the risk assessment of sulfolane continues, according to the authors, the results could aid in the interpretation of previous and future toxicity data. Ultimately, this line of research may provide health guidance on exposure to sulfolane. (JW)
Citation: Shipkowski KA, Cora MC, Cesta MF, Robinson VG, Waidyanatha S, Witt KL, Vallant MK, Fallacara DM, Hejtmancik MR, Masten SA, Cooper SD, Fernando RA, Blystone CR. 2021. Comparison of sulfolane effects in Sprague Dawley rats, B6C3F1/N mice, and Hartley guinea pigs after 28 days of exposure via oral gavage. Toxicol Rep 8:581–591.
N terminus region of Orai1 is required for NFAT activation
NIEHS researchers led a team that found the N terminus region of Orai1, a calcium channel protein, is required for activation of nuclear factor of activated T cells (NFAT). NFAT is an important transcription factor that regulates the expression of various chemokines and cytokines involved in immune responses. The finding provides new insight into therapeutic targets for immunosuppressant drugs.
Calcium signaling is vital for the function of immune cells. After an antigen stimulation, calcium enters immune cells through calcium channels and triggers downstream inflammatory responses. As a component of store operated calcium channels, Orai1 is essential for NFAT activation in T cells through interaction with the scaffolding protein AKAP79. However, little is known about the protein region of Orai1 that interacts with AKAP79.
In this study, the researchers mapped the AKAP79 association region (AKAR) on Orai1 by examining the effect of various deletion mutants on AKAP79 interaction and NFAT activation. They found that the AKAR was contained in the N terminus of Orai1, but not Orai2 or Orai3. They also reported the NMR structure of AKAR peptide, which could compete with AKAR on Orai1 to suppress Orai1-AKAP79 interaction and NFAT-mediated cytokine production. The study suggests AKAR on Orai1 could be targeted for development of new immunosuppressants. (QX)
Citation: Kar P, Lin YP, Bhardwaj R, Tucker CJ, Bird GS, Hediger MA, Monico C, Amin N, Parekh AB. 2021. The N terminus of Orai1 couples to the AKAP79 signaling complex to drive NFAT1 activation by local Ca2+ entry. Proc Natl Acad Sci U S A 118(19):e2012908118.
Male hormones protect against gastric inflammation
Male hormones can protect from inflammation and pre-cancerous conditions in the stomach, according to a study by NIEHS scientists. The study offers novel mechanistic insight into how male hormones regulate stomach inflammation by restraining specialized immune cells.
The authors observed that glucocorticoids, a type of steroid hormone produced by adrenal glands, is required to protect female mice from stomach inflammation. However, in male mice, they found that in addition to glucocorticoids, male sex hormones provide an additional layer of protection against stomach inflammation. The researchers found that the inflammatory response from specific immune cells called type 2 innate-lymphoid cells (ILC2) drives the development of gastric inflammation. Importantly, the study showed that male sex hormones directly repress the proinflammatory state of ILC2, thereby preventing harmful inflammation.
While it is known that autoimmune diseases are more prevalent in females than males, the role of male hormones in inflammation has not been explored. This study shows that male hormones can restrict hyperinflammatory responses in the stomach and could prove beneficial in designing treatment of gastric inflammation based on sex. (PR)
Citation: Busada JT, Peterson KN, Khadka S, Xu X, Oakley RH, Cook DN, Cidlowski JA. 2021. Glucocorticoids and androgens protect from gastric metaplasia by suppressing group 2 innate lymphoid cell activation. Gastroenterology; doi: 10.1053/j.gastro.2021.04.075 [Online 7 May 2021]. (Story)
Low vitamin D may increase heavy metal levels in pregnant women
NIEHS researchers and their collaborators found that low levels of 25-hydroxyvitamin D (25OHD), the circulating biomarker of vitamin D, were associated with elevated levels of certain heavy metals in pregnant women. The work is important because in utero exposure to heavy metals can result in negative health impacts for a fetus.
Vitamin D is an essential dietary nutrient that aids in the absorption of calcium and the development of healthy bones. While vitamin D is recommended during pregnancy, some studies have linked vitamin D to higher levels of toxic metals.
The scientists conducted a prospective study on a cohort of 381 pregnant women to investigate the potential positive correlation between 25OHD levels during the first trimester and heavy metal levels in the late, second trimester. Using a chemiluminescence immunoassay, 25OHD was measured in plasma samples taken at 10 weeks of gestation. Urine samples taken at 26 weeks of gestation were used for measurement of 17 metals and elements. Upon analysis, the investigators observed elevated tin, lead, molybdenum, and tungsten levels in pregnant women with low 25OHD. The authors said that given conflicting evidence, additional research should be done to confirm how vitamin D affects metal levels in pregnant women. (NA)
Citation: Jukic AMZ, Kim SS, Meeker JD, Weiss ST, Cantonwine DE, McElrath TF, Ferguson KK. 2021. A prospective study of maternal 25-hydroxyvitamin D (25OHD) in the first trimester of pregnancy and second trimester heavy metal levels. Environ Res 199:111351.
Smoking and asthma interact with gene variants to reduce lung function
Genetic susceptibility has a larger effect on reduced lung function in the presence of smoking or asthma, according to NIEHS researchers and their collaborators. Their findings support the use of Genetic Risk Scores (GRSs) to study how environmental factors interact with genetic susceptibility.
Data came from a case-control study of asthma consisting of 2,844 adults nested in a U.S. agricultural cohort. GRSs, which combine data across single nucleotide polymorphisms from large-scale genome-wide association studies, were developed for three spirometric lung function traits: FEV1, which refers to the amount of air exhaled in the first second; FVC, which measures the total exhaled amount; and their ratio, FEV1/FVC. The researchers used linear regression to estimate associations of each trait with its GRS and to estimate interactions.
All three traits were significantly lower among current and former smokers compared to never smokers and among asthmatics compared to non-asthmatics. The three traits were also highly associated with their GRSs. The scientists observed significant interactions between GRS for reduced FEV1/FVC and smoking status and asthma, but they did not find a significant interaction between any GRS and house dust endotoxin. The research sheds light on potential mechanisms responsible for the interactions between genetic variants and exposure to smoking or asthma in relation to lung function. (SM)
Citation: Sikdar S, Wyss AB, Lee MK, Hoang TT, Richards M, Beane Freeman LE, Parks C, Thorne PS, Hankinson JL, Umbach DM, Motsinger-Reif A, London SJ. 2021. Interaction between Genetic Risk Scores for reduced pulmonary function and smoking, asthma and endotoxin. Thorax; doi: 10.1136/thoraxjnl-2020-215624 [Online 7 May 2021].
(Nicholas Alagna is an Intramural Research Training Award [IRTA] postbaccalaureate fellow in the NIEHS Mechanisms of Mutation Group. Sanya Mehta is an IRTA postbaccalaureate fellow in the NIEHS Matrix Biology Group. Prashant Rai, Ph.D., is a visiting fellow in the NIEHS Clinical Investigation of Host Defense Group. Janelle Weaver, Ph.D., is a contract writer for the NIEHS Office of Communications and Public Liaison. Qing Xu is a biologist in the NIEHS Metabolism, Genes, and Environment Group.)
