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Environmental Factor, August 2012

Intramural papers of the month

By Anshul Pandya, Sonika Patial, and Sheila Yong

Agricultural Health Study examines fungal sensitization in farmers

Scientists from NIEHS, the Centers for Disease Control and Prevention, and the National Cancer Institute have determined that farmers who grew tobacco, orchard fruit, or raised animals, particularly cattle, were more likely to be sensitized to fungi than farmers involved in other farming activities. The research was published in the Journal of Allergy and Clinical Immunology, and explored the associations between farming activities and fungal sensitization in farmers in the Agricultural Health Study.

Serum samples from 677 male subjects in the study were screened for fungal positivity by fluoroenzymeimmunoassay. These participants were pesticide applicators who had completed three questionnaires about their agricultural and medical history. The prevalence of fungal sensitization turned out to be approximately 4 percent, much lower than the general U.S. population. In addition to tobacco, orchard fruit, and cattle farmers being more fungal sensitized than other farmers, soybean, corn, and other grain farmers were also positively associated with fungal sensitization, although the association was not statistically significant. (AP)

CitationEndres SM, Green BJ, Henneberger PK, Germolec DR, Bledsoe TA, Beezhold DH, London SJ, Alavanja MC, Beane Freeman LE, Hoppin JA. 2012. Fungal and atopic sensitization are low among farmers in the Agricultural Health Study. J Allergy Clin Immunol 130(1):267-270.

DNA polymerase zeta directly promotes somatic hypermutation in B lymphocytes

Researchers from NIEHS and the University of Louisville School of Medicine recently revealed a direct role for DNA polymerase zeta (Pol zeta) in facilitating somatic hypermutation (SHM) in B cells, a process critical in enhancing antibody affinity to a specific antigen.

The team used a pair of B cell-specific Pol zeta mutant mouse models consisting of a Rev3 deletion, which deleted the catalytic domain of Pol zeta, and a Rev3L2610F knock-in mutation. Since other studies reported that a homologous substitution in yeast enhanced spontaneous ultraviolet-induced mutagenesis, the scientists hypothesized that this Pol zeta mutation would enhance SHM.

They found, that while both mutations did not alter B-cell development and germinal center formation in these mice, the Rev3-deleted B cells proliferated more slowly and were much less efficient in undergoing SHM upon antigenic stimulation, compared to Rev3L2610F B cells and wildtype controls. Furthermore, Rev3-deleted B cells suffered an activation defect, as proportions of GL7+ B cells were markedly reduced in both the spleen and Peyer’s patch. Their findings suggest that the Rev3L2610F mutant of Pol zeta enhances SHM and subsequently increases the affinity-enhancing mutations of B cells toward specific antigens. These models are useful for understanding how the immune system fights pathogens with antigens that are constantly changing. (SY)

CitationDaly J, Bebenek K, Watt DL, Richter K, Jiang C, Zhao ML, Ray M, McGregor WG, Kunkel TA, Diaz M. 2012. Altered Ig hypermutation pattern and frequency in complementary mouse models of DNA polymerase zeta activity. J Immunol 188(11):5528-5537.

SIRT1 regulates hepatic bile acid homeostasis

According to a recent study, deletion of the hepatic SIRT1 gene reduces the expression of a nuclear farnesoid X receptor (FXR), which regulates the homeostasis of bile acid. The report, published by researchers from NIEHS, the University of North Carolina at Chapel Hill, and the University of Illinois at Urbana-Champaign, provides a direct link between SIRT1 and cholesterol gallstone disease.

The SIRT1 gene encodes for mammalian sirtuin-1 protein, a NAD-dependent deacetylase, which plays a key role in linking nutrient signals to metabolic homeostasis in animals. Using quantitative polymerase chain reaction (qPCR) and the luciferase assay, the authors demonstrate that SIRT1 regulates the expression of FXR through hepatocyte nuclear factor 1alpha (HNF1alpha). In addition, they found that the liver cell-specific deletion of SIRT1 upset the normal functioning of bile acid metabolism and increased the probability of the development of cholesterol gallstones in mice on a lithogenic diet, one specially designed to increase the likelihood of stone formation.

These findings indicate that the SIRT1 gene plays an important role in regulating bile acid homeostasis in mammalian liver cells, through the HNF1alpha/FXR signaling pathway. By modulating the activity of SIRT1, scientists could develop novel therapies to prevent the formation of cholesterol gallstones and other metabolic diseases linked to type 2 diabetes. (AP)

CitationPurushotham A, Xu Q, Lu J, Foley JF, Yan X, Kim DH, Kemper JK, Li X. 2012. Hepatic deletion of SIRT1 decreases hepatocyte nuclear factor 1 alpha/farnesoid X receptor signaling and induces formation of cholesterol gallstones in mice. Mol Cell Biol 32(7):1226-1236.

NRF2 regulates retinoid X receptor alpha

Researchers at NIEHS and The Hamner Institutes found a potential link between antioxidant responsive transcription factor NRF2 and retinoid X receptor alpha (RXRA) in human lymphocytes and adipocytes. This novel finding suggests that RXRA as a NRF2 responsive gene has potential implications in the cellular response to sulforaphane (SFN) treatment and lipid synthesis.

The aim of the study was to identify novel genes that are regulated by NRF2 in human cells. The researchers activated NRF2 with the dietary antioxidant, SFN, followed by chromatin-immunoprecipitation (ChIP) and high-throughput analysis, using techniques such as parallel sequencing, microarray technology, siRNA, and bioinformatics.

The results not only validated many known targets of NRF2 that are involved in processes, such as oxidant neutralization and xenobiotic metabolism, but also identified novel targets involved in pathways such as iron metabolism, cell death, immune response, and retinoid signaling by the nuclear receptor RXRA. RXRA is a binding partner for PparG, the master regulator of adipocyte differentiation, which has also been recently identified as a NRF2-regulated gene by NIEHS researchers. Furthermore, treatment of a preadipocyte cell line, 3T3-L1, with SFN led to the inhibition of differentiation into mature adipocytes, suggesting that NRF2-dependent perturbation of RXRA and PparG might be involved. (SP)

CitationChorley BN, Campbell MR, Wang X, Karaca M, Sambandan D, Bangura F, Xue P, Pi J, Kleeberger SR, Bell DA. 2012. Identification of novel NRF2-regulated genes by ChIP-Seq: influence on retinoid X receptor alpha. Nucleic Acids Res; doi:10.1093/nar/gks409 [Online 11 May 2012].

(Anshul Pandya, Ph.D., is an Intramural Research Training Award fellow in the NIEHS Laboratory of Neurobiology. Sonika Patial, D.V.M., Ph.D., and Sheila Yong, Ph.D., are visiting fellows in the NIEHS Laboratory of Signal Transduction.)

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