Papers of the Month
By Victoria Placentra, Prashant Rai, Saniya Rattan, Nancy Urbano, and Qing Xu
NTP finds maternal exposure to PBDEs causes liver toxicity in rat pups
Division of the National Toxicology Program (NTP) researchers revealed that exposure to pentabromodiphenyl ethers (PBDEs), which are a mixture of chemicals used as flame retardants, alters the expression profile of liver genes in newborn rat pups. The findings identify early biomarkers of PBDE toxicity that may help predict the risk of toxicity and cancer after long-term exposure.
PBDEs were widely used in household products, including electronic devices, furniture, and textiles, but due to their harmful effects on the thyroid, liver, and developing brain, they were phased out. However, PBDE constituents can still be detected in the environment and in body fluids such as breast milk, which suggests a potential exposure to infants. Because the liver is one of the first organs that respond to toxicants, the authors wanted to determine whether exposure to PBDEs in utero could induce gene expression alterations in the livers of neonatal rat pups.
The scientists treated pregnant rats with either a PBDE mixture called DE-71, or its primary constituent, PBDE-47, which is the most dominant congener detected in human tissues. They found decreased thyroid hormone levels in the pups. Global gene expression alterations involved in detoxification, the antioxidant system, and membrane transport were observed in the pups. These early toxicogenomic indicators may be used to help prioritize chemicals for a more complete toxicity and cancer risk evaluation. (QX)
Citation: Dunnick JK, Shockley KR, Morgan DL, Travlos GS, Gerrish K, Ton TT, Wilson R, Brar SS, Brix AE, Waidyanatha S, Mutlu E, Pandiri AKR. 2019. Hepatic transcriptomic patterns in the neonatal rat after pentabromodiphenyl ether exposure. Toxicol Pathol; doi: 10.1177/0192623319888433 [Online 12 December 2019].
Noncanonical autophagy required for UV-induced immunosuppression
A team of NIEHS researchers demonstrated that the noncanonical autophagic pathway called LC3-associated phagocytosis (LAP) is essential for the immunosuppressive effects of ultraviolet (UV) light exposure.
Inflammation is an immune response to stress, and immunosuppression assists the return to homeostasis after an immune response. Autophagy, an evolutionarily conserved survival and quality control pathway, is involved in immunosuppression, but the mechanism underlying its role is not well understood. Defects in autophagy are associated with several disease states. LAP is a noncanonical autophagic pathway critical for immunosuppression and requires the protein rubicon (RUBCN).
To study the role of LAP and RUBCN in immunosuppression, scientists developed mouse strains that lacked the RUBCN gene. These Rubcn-null mice were exposed to UV light, then the team measured inflammation and the subsequent mRNA expression levels of genes associated with RUBCN and inflammation. The Rubcn-null mice exposed to UV light displayed hyperinflammation, which indicated that RUBCN is necessary to activate the immunosuppressive action of UV light.
The results from this study contribute to the understanding of how UV light suppresses inflammation, which is not well understood. The ability to target LAP may have implications for immunotherapies and other treatments of inflammation. (VP)
Citation: Sil P, Suwanpradid J, Muse G, Gruzdev A, Liu L, Corcoran DL, Willson CJ, Janardhan K, Grimm S, Myers P, Degraff LM, MacLeod AS, Martinez J. 2019. Non-canonical autophagy in dermal dendritic cells mediates immunosuppressive effects of UV exposure. J Allergy Clin Immunol; doi: 10.1016/j.jaci.2019.11.041 [Online 11 December 2019].
Two methods ensure use of correct and undamaged DNA nucleotides
According to NIEHS scientists and their University of Michigan collaborators, DNA ligase 1 (LIG1) uses magnesium and aprataxin to ensure that nucleotides that are incorporated into the DNA strand are correct and undamaged. LIG1 is the enzyme responsible for joining DNA ends during replication, recombination, and repair. This work contributes to the overall understanding of the mechanism behind DNA maintenance.
To better understand the characteristics of LIG1, the scientists used X-ray crystallography to generate high-resolution structures of LIG1 and mutant LIG1. They performed kinetic analyses to test the enzymes’ ability to bind properly paired or damaged DNA nucleotides. These experiments led the researchers to identify a novel binding site within LIG1 that uses magnesium. This magnesium-reinforced binding site can discriminate between damaged and undamaged DNA during adenylyl transfer and nick-sealing ligation steps. The scientists also showed that the protein aprataxin, which recognizes DNA damage or lesions, intercepts damaged DNA nucleotides and suppresses LIG1 activity. These two approaches act to promote the incorporation of correct and undamaged nucleotides, known as DNA fidelity. (SR)
Citation: Tumbale PP, Jurkiw TJ, Schellenberg MJ, Riccio AA, O’Brien PJ, Williams RS. 2019. Two-tiered enforcement of high-fidelity DNA ligation. Nat Commun 10(1):5431.
Gene variants linked to immune-mediated diseases in different ethnicities
Using data from participants in the Environmental Polymorphisms Registry, NIEHS researchers and their collaborators found that variations of two genes — the aryl hydrocarbon receptor nuclear translocator (ARNT) and the protein tyrosine phosphatase, nonreceptor type 22 (PTPN22) — are associated with immune-mediated diseases (IMDs) in several ethnicities. Because ARNT and PTPN22 are sensitive to environmental factors, this study is the first to demonstrate across ethnicities the combined role of these genes and environmental changes in the development of immune-related conditions, such as autoimmune disease, allergies, and asthma.
The study included 3,731 participants. Its goal was to determine whether the replacement of a nucleotide in DNA, known as a single nucleotide polymorphism (SNP), was associated with IMD. The scientists theorized that SNPs led to the dysregulation of the normal immune response. The authors genotyped the participants, looking at 14 SNPs to determine whether they were associated with IMD. They compared the frequency of these SNPs in African American, Caucasian, and Hispanic participants with the incidence of IMD using METAL and MANTRA, two methods of transethnic meta-analyses.
The researchers found that two ARNT SNPs were associated with autoimmune disease, whereas two PTPN22 SNPs were associated with either IMD and allergic disease or autoimmune disease. The research team stressed that further studies are needed to confirm the data and to explore the mechanisms behind them. (NU)
Citation: Schurman SH, O’Hanlon TP, McGrath JA, Gruzdev A, Bektas A, Xu H, Garantziotis S, Zeldin DC, Miller FW. 2019. Transethnic associations among immune-mediated diseases and single-nucleotide polymorphisms of the aryl hydrocarbon response gene ARNT and the PTPN22 immune regulatory gene. J Autoimmun 107:102363.
Using permanent hair dye or straighteners may raise breast cancer risk
A team of NIEHS scientists found that use of permanent hair dyes and chemical hair straighteners was associated with an increased risk of breast cancer in women.
Of 46,709 women enrolled in the Sister Study, 2,794 participants developed breast cancer. The scientists found that, overall, women who used permanent hair dye during the previous 12 months had a 9% higher breast cancer risk compared with women who did not use permanent hair dye. For white women who used permanent dyes every five to eight weeks, their risk of breast cancer increased by 8%, but among African American women who were equally frequent users, the risk jumped to 60%. The research team found little to no increase in breast cancer risk for semi-permanent or temporary dye use.
The team found that participants who had used chemical straighteners any time in the past 12 months experienced an approximately 18% higher risk of breast cancer. Women who used straighteners more frequently, every five to eight weeks, had a 30% increase in breast cancer risk. Although this association was similar in white and African American women, straightener use was much more common among African American women. (PR)
Citation: Eberle CE, Sandler DP, Taylor KW, White AJ. 2019. Hair dye and chemical straightener use and breast cancer risk in a large U.S. population of black and white women. Int J Cancer; doi: 10.1002/ijc.32738 [Online 3 December 2019]. (Story)
(Victoria Placentra is an Intramural Research Training Award [IRTA] postbaccalaureate fellow in the NIEHS Mutagenesis and DNA Repair Regulation Group. Prashant Rai, Ph.D., is a visiting fellow in the NIEHS Clinical Investigation of Host Defense Group. Saniya Rattan, Ph.D., is an IRTA fellow in the NIEHS Reproductive Developmental Biology Group. Nancy Urbano is an IRTA postbaccalaureate fellow in the NTP Predictive Toxicology and Screening Group. Qing Xu is a biologist in the NIEHS Metabolism, Genes, and Environment Group.)