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Papers of the month

Intramural
By David Banks, Mahita Kadmiel, Gabriel Knudsen, Georgia Roberts, and Qing Xu

NTP reduces animal use, one assay at a time — skin sensitization testing

Researchers working with the National Toxicology Program (NTP) Interagency Center for the Evaluation of Alternative Methods have advanced the integration of nonanimal models to predict chemical skin sensitization. Skin sensitization testing is currently the most common use of animals in chemical safety assessment, and these new approaches will help eliminate animal use.

The integrated decision strategy combines various data that represent key events in skin sensitization to increase the predictive power of nonanimal methods. The researchers used a database of 120 chemicals to train and evaluate six computer models, each with six sets of variables, to optimize accuracy of predictions while minimizing inputs. The variables included in vitro assays, in silico modeling, and chemical properties. Model accuracy was determined based on results in the in vivo local lymph node assay, a gold standard for skin sensitization testing.

Using this approach, the researchers identified seven models for predicting skin sensitization that have higher accuracy than currently recommended nonanimal test methods. This approach advances the use of nonanimal models in identifying skin sensitization hazards, but additional work is needed to address chemical potency, which is crucial for use in risk assessment activities. (GR)

Citation: Strickland J, Zang Q, Kleinstreuer N, Paris M, Lehmann DM, Choksi N, Matheson J, Jacobs A, Lowit A, Allen D, Casey W. 2016. Integrated decision strategies for skin sensitization hazard. J Appl Toxicol 36(9):1150–1162.

Pesticide exposure linked to respiratory symptoms in farmers

Researchers at NIEHS, North Carolina State University, and the National Cancer Institute have established a link between current pesticide use and wheeze in male farmers.

To determine if pesticide exposure was associated with respiratory problems, the scientists used the 2005¬ 2010 interview data from the Agricultural Health Study (AHS), a study of farmers in North Carolina and Iowa. Approximately 22,000 male farmers who worked with pesticides and participated in the AHS were assessed for allergic wheeze and non-allergic wheeze.

The study evaluated 78 pesticides, including herbicides, insecticides, fungicides, and others. Age, body mass index, smoking status, duration of pesticide use, and geographic location were some of the variables taken into consideration in analysis of the data. Using statistical models to compare farmers with no wheeze to farmers with wheeze, the researchers found that 19 pesticides were associated with allergic wheeze, 21 pesticides were associated with non-allergic wheeze, and 11 pesticides were associated with both. The findings found that several pesticides commonly used on farms and in homes had adverse respiratory effects. (MK)

Citation: Hoppin JA, Umbach DM, Long S, London SJ, Henneberger PK, Blair A, Alavanja M, Beane Freeman LE, Sandler DP. 2016. Pesticides are associated with allergic and non-allergic wheeze among male farmers. Environ Health Perspect; doi:10.1289/EHP315 [Online 6 July 2016].

Surplus folate during pregnancy may increase child asthma risk

Collaborating with an international team of researchers, NIEHS scientists have determined a direct link between elevated maternal folate intake and an increased risk of asthma during childhood.

Total folate intake included both dietary and supplemental folate consumption, and this measurement was validated against plasma folate levels at 18 weeks of gestation. Asthma at age seven years was defined by either maternal report or asthma medications administered at least twice in one year. By combining data from the Norwegian Mother and Child Cohort Study and Norwegian Prescription Database, researchers achieved robust follow-up. Risk of childhood asthma increased by approximately 20 percent between the highest and lowest quintiles of total folate intake.

Because adequate folate intake is important for preventing neural tube defects, the World Health Organization recommends supplemental folate intake during pregnancy. The NIEHS researchers and colleagues have determined that supplemental intake at or above the recommended dosage, in combination with a folate-rich diet, achieves a total folate intake level associated with a slightly increased risk of pediatric asthma. (DB)

Citation: Parr CL, Magnus MC, Karlstad O, Haugen M, Refsum H, Ueland PM, McCann A, Nafstad P, Haberg SE, Nystad W, London SJ. 2016. Maternal folate intake during pregnancy and childhood asthma in a population based cohort. Am J Respir Crit Care Med; doi:10.1164/rccm.201604-0788OC [Online 12 August 2016].

Soy infant formula induces epigenetic changes in girls

Using vaginal cell data from the Infant Feeding and Early Development Study, NIEHS researchers demonstrated that infant girls who were fed soy formula showed increased DNA methylation in three CpG sites of the proline rich 5 like (PRR5L) gene. Analogous results were found in mice exposed to genistein, the principal phytoestrogen found in soy. Because phytoestrogens affect the development of rodent and human reproductive systems, this work has important implications in the study of early life exposures.

To determine whether early life genistein exposure led to epigenetic alterations in reproductive tract tissues, the authors compared DNA methylation patterns in vaginal epithelial cells serially collected during a nine-month period from infants fed soy or cow milk formula. Parallel studies were conducted using CD-1 mice administered genistein subcutaneously.

The researchers found methylation of three CpGs near the transcription start site in the human PRR5L gene that were highly significant at 126 days after birth in girls who were fed soy formula girls compared girls who had cow formula. Neonatal mice that were exposed to genistein had significantly lower PRR5L gene expression, consistent with the increased promoter methylation and repression observed in girls. These results support the hypothesis that epigenetic changes may act as a mechanism for health effects detected later in life. (GK)

Citation: Harlid S, Adgent M, Jefferson WN, Panduri V, Umbach DM, Xu Z, Stallings VA, Williams CJ, Rogan WJ, Taylor JA. 2016. Soy formula and epigenetic modifications: analysis of vaginal epithelial cells from infant girls in the IFED Study. Environ Health Perspect; doi:10.1289/EHP428 [Online 19 August 2016].

Downstream antisense transcription contributes to gene regulation

NIEHS researchers and colleagues revealed that downstream antisense transcription, in which RNA is transcribed from DNA opposite of the sense strand, correlates with distinct genomic features of nearby DNA promoters, where gene transcription is initiated. The study provides clues to the biological functions of antisense RNA in gene regulation.

Gene expression starts with transcription of sense DNA to protein-coding messenger RNA from transcription start sites (TSSs) adjacent to promoters. TSSs are also found in antisense DNA, but their roles remain unclear. Previous research characterized antisense transcription initiated upstream of gene TSSs, so the authors of this study attempted to investigate genetic and epigenetic settings around downstream antisense TSSs (daTSSs).

Using next-generation sequencing in human breast cancer cells, the researchers found that downstream antisense transcription is widespread in the genome. DaTSSs are located between regularly spaced nucleosomes consisting of histone proteins wrapped by DNA, and the region between daTSSs and gene TSSs is enriched with histone modifications that indicate active promoters. In constrast to the results from another study, the daTSSs did not inhibit gene expression. The research also found that daTSSs correlate with other components of transcriptional machinery, such as transcription factors and chromatin remodelers. The findings suggest that downstream antisense transcription is an integral part of the gene regulatory network. (QX)

Citation: Lavender CA, Cannady KR, Hoffman JA, Trotter KW, Gilchrist DA, Bennett BD, Burkholder AB, Burd CJ, Fargo DC, Archer TK. 2016. Downstream antisense transcription predicts genomic features that define the specific chromatin environment at mammalian promoters. PLoS Genet 12(8):e1006224.

(David Banks is a postbaccalaureate Intramural Research and Training Award (IRTA) fellow in the NIEHS Receptor Biology Group. Mahita Kadmiel, Ph.D., is an IRTA fellow in the NIEHS Molecular Endocrinology Group. Gabriel Knudsen, Ph.D., is a Cancer Research Training Award fellow in the National Cancer Institute, Center for Cancer Research, Laboratory of Toxicology and Toxicokinetics. Georgia Roberts, Ph.D., is an IRTA fellow in the General Toxicology and Cancer Group. Qing Xu is a biologist in the NIEHS Metabolism, Genes, and Environment Group.)