Papers of the Month
By Robin Arnette, Kathleen Foley, Stephani Kim, Rajneesh Pathania, and Salahuddin Syed
NTP reports flame retardant increases fat cell development
Using a mouse cell line, researchers from the National Toxicology Program (NTP) and the University of California, Irvine found that exposure to a common flame retardant, tetrabromobisphenol A (TBBPA), may be linked to early adipogenesis and to lipogenesis, or fat formation. Adipogenesis is the formation of fat cells from cells called preadipocytes, and lipogenesis is the formation of fat.
Obesity is a risk factor for many chronic diseases, including cardiovascular disease and diabetes. Although obesity is usually associated with a high caloric diet, recent studies have shown that exposure to certain environmental chemicals may play a role in increased weight gain. TBBPA, which is found in electronics, paints, textiles, and household dust, is one of those suspected chemicals.
Researchers exposed mouse preadipocytes to different concentrations of TBBPA for eight days and observed an increase in the number of fat cells and fat accumulation. They found that TBBPA decreases the expression of genes that prevent preadipocytes from becoming mature adipocytes and increases the expression of key early genes that eventually activate PPARgamma, which is a known regulator for adipogenesis. Because TBBPA is one of many chemicals that may be involved in the increased formation of fat and fat cells, these novel pathways are of interest to scientists. TBBPA is commonly found in homes and can be detected in human blood, breast milk, and fat. (SK)
Citation: Chappell VA, Janesick A, Blumberg B, Fenton SE. 2018. Tetrabromobisphenol-A promotes early adipogenesis and lipogenesis in 3T3-L1 cells. Toxicol Sci 166(2):332–344.
Sinus surgery decreases aspirin sensitivity in AERD patients
The removal of nasal polyps using endoscopic sinus surgery (ESS) results in decreased aspirin sensitivity in people with aspirin-exacerbated respiratory disease (AERD), according to NIEHS researchers and their collaborators. AERD is a chronic medical condition characterized by asthma, nasal polyps, and respiratory sensitivity to aspirin and other nonsteroidal anti-inflammatory drugs.
The objective of this study was to investigate the effects of ESS on the severity of aspirin-induced reactions and to determine the factors associated with patient outcome. Before ESS, aspirin challenges given to 28 AERD patients resulted in hypersensitivity; however, after ESS, reactions to aspirin were less severe. Twelve of 28 patients, or 43 percent, had no detectable reaction to aspirin after ESS. A lack of clinical reaction to aspirin was associated with lower peripheral blood eosinophilia, lower urinary leukotriene E4 levels after aspirin challenge, and a lower plasma prostaglandin D2 to prostaglandin E2 ratio.
The findings, which appeared in the Journal of Allergy and Clinical Immunology: In Practice, demonstrate that sinus surgery results in decreased aspirin sensitivity and a decrease in plasma and urine leukotriene, as well as prostaglandin levels in AERD patients. (RP)
Citation: Jerschow E, Edin ML, Chi Y, Hurst B, Abuzeid WM, Akbar NA, Gibber M, Fried MP, Han W, Pelletier T, Ren Z, Keskin T, Gottlieb GR, Lih FB, Gruzdev A, Bradbury JA, Schuster V, Spivack S, Rosenstreich D, Zeldin DC. 2018. Sinus surgery is associated with a decrease in aspirin-induced reaction severity in AERD patients. J Allergy Clin Immunol Pract; doi:10.1016/j.jaip.2018.12.014 [Online 20 December 2018].
Several factors regulate efficiency of human iPSC reprogramming
Researchers at NIEHS have found that epigenetic enzymes, age, and ancestry affect the reprogramming efficiency of human-induced pluripotent stem cells (iPSCs). Humans possess pluripotent cells, embryonic stem cells, and adult stem cells that can differentiate into the multiple cell types that make up the human body. iPSCs are a type of pluripotent stem cell that can be generated from adult cells, in this case, dermal fibroblasts (DFs), by inducing the expression of pluripotency factors, such as OCT4, SOX2, KLF4, and MYC proteins. Current studies have evaluated iPSC reprogramming efficiency in small sample sizes, but larger sample sizes are needed to better see the relationship between demographic characteristics and reprogramming.
To analyze reprogramming efficiency, the authors created 240 iPSC lines from human DFs from 80 healthy donors. They found that several of the SWI/SNF chromatin remodeling complex protein subunits, BRG1, BAF155, and BAF60a, showed increased expression and were strongly correlated with iPSC reprogramming efficiency. In addition, high-efficiency iPSC reprograming was negatively correlated with donor age, positively correlated with African American descent, and uncorrelated with donor sex. Generating a large, diverse, and healthy donor cohort will allow for the creation of sophisticated cell-based models for mechanism of action studies, pharmaceutical development, and toxicity assessments. (SS)
Citation: Mackey LC, Annab LA, Yang J, Rao B, Kissling GE, Schurman SH, Dixon D, Archer TK. 2018. Epigenetic enzymes, age, and ancestry regulate the efficiency of human iPSC reprogramming. Stem Cells 36(11):1697–1708.
Individual metals and mixtures associated with preterm birth
Trace amounts of metals measured in urine samples of pregnant women have been linked to a higher risk of preterm birth (PTB) or being born before 37 weeks of gestation. The study, performed by NIEHS scientists and their collaborators, analyzed 17 trace metals individually in relation to preterm birth and also in mixtures using the statistical methods elastic net (ENET) regularization and principal components analysis (PCA). The team determined that copper found in urine samples from mothers in their third trimester of pregnancy was the metal most associated with preterm birth, which was shown in individual models and also shown when using ENET.
PCA was used to identify groups of metals within the mixture linked to preterm birth. This method showed that a variable derived from urinary arsenic, mercury, and tin concentrations was associated with preterm birth, which suggested a cumulative effect of these compounds. The research was part of the LIFECODES birth cohort, an on-going study conducted at Brigham and Women’s Hospital in Boston. (RA)
Citation: Kim SS, Meeker JD, Carroll R, Zhao S, Mourgas MJ, Richards MJ, Aung M, Cantonwine DE, McElrath TF, Ferguson KK. 2018. Urinary trace metals individually and in mixtures in association with preterm birth. Environ Int 121(Pt 1):582–590.
Increased risk of breast cancer after childbirth
Not having children is a well-established risk factor for breast cancer. However, researchers from NIEHS, the University of North Carolina at Chapel Hill, and the Institute of Cancer Research, London reported an increased risk of breast cancer following childbirth that peaked at five years after birth. Compared to women who never had children, women who had given birth had an 80 percent higher chance of developing breast cancer five years later. The increased risk after pregnancy lasted an average of 24 years before childbirth became protective.
The team pooled data from 15 prospective cohort studies from around the world to study factors related to breast cancer before age 55 years. Breast cancer is rare in young women, so risk factors for young-onset breast cancer are not well studied. The researchers found that the relative risk for breast cancer following childbirth was greater for women who were older at first birth, had more births, or had a family history of breast cancer. The risk was the same whether or not women breastfed.
Although the actual number of breast cancers expected after childbirth is small, these findings could help women and their doctors make decisions about when to start breast cancer screening. (KF)
Citation: Nichols HB, Schoemaker MJ, Cai J, Xu J, Wright LB, Brook MN, Jones ME, Adami H-O, Baglietto L, Bertrand KA, Blot WJ, Boutron-Ruault M-C, Dorronsoro M, Dossus L, Eliassen AH, Giles GG, Gram IT, Hankinson SE, Hoffman-Bolton J, Kaaks R, Key TJ, Kitahara CM, Larsson SC, Linet M, Merritt MA, Milne RL, Pala V, Palmer JR, Peeters PH, Riboli E, Sund M, Tamimi RM, Tjonneland A, Trichopoulou A, Ursin G, Vatten L, Visvanathan K, Weiderpass E, Wolk A, Zheng W, Weinberg CR, Swerdlow AJ, Sandler DP. 2018. Breast cancer risk after recent childbirth: a pooled analysis of 15 prospective studies. Ann Intern Med 170(1):22–30. (Story)