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Papers of the month

Intramural
By Tara Ann Cartwright, Deacqunita Diggs, Emily Mesev, Simone Otto, and Qing Xu

NTP studies developmental effects of chemical toxicants on C. elegans and other species

A research team, led by National Toxicology Program scientists, used the nematode Caenorhabditis elegans (C. elegans) to screen 968 chemicals from the ToxCast Phase I and Phase II libraries of the U.S. Environmental Protection Agency National Center for Computational Toxicology. The scientists determined which chemicals inhibited larval development and growth, and then compared their results to developmental toxicity data from rat, rabbit, and two zebrafish studies.

The nematode results agreed with one zebrafish assay for approximately 80 percent of the ToxCast chemicals; agreement was less than 60 percent with another assay. More importantly, when C. elegans or zebrafish data were used to predict mammalian outcomes, the agreement was approximately 50 percent, while agreement between rabbit and rat chemical toxicity data was also low at 58 percent.

C. elegans has been proven to be a useful animal model to determine the consequence of exposures to a variety of environmental chemicals. Toxicity data from this species may be combined with that from higher organisms when conducting mammalian in vivo studies. The data from lower organisms, along with in vitro data from human cell culture studies, may provide scientists with useful tools for predicting adverse human responses associated with exposure to potential environmental toxicants. (DD)

Citation: Boyd WA, Smith MV, Co CA, Pirone JR, Rice JR, Shockley KR, Freedman JH. 2015. Developmental effects of the ToxCast Phase I and II chemicals in Caenorhabditis elegans and corresponding responses in zebrafish, rats, and rabbits. Environ Health Perspect; doi:10.1289/ehp.1409645 [Online 23 October 2015].

Xenobiotics and antinuclear antibodies

NIEHS scientists and their collaborators conducted research on the association between exposure to environmental chemicals and selected mixtures, in relation to the presence of antinuclear antibodies (ANA), a biomarker of autoimmunity, in a sample of the U.S. population. This comprehensive study analyzed National Health and Nutrition Examination Survey (NHANES) data collected by the U.S. Centers for Disease Control and Prevention from 1999 to 2004. ANA detection was determined by testing blood serum specimens from NHANES participants using indirect immunofluorescence.

The study provided little evidence that ANA were associated with exposure to any of the 21 dioxin-like chemicals or the 19 mixtures analyzed. In contrast, a positive association between ANA and exposure to triclosan, a non-dioxin-like chemical found in many consumer products, was observed in males. This positive association appeared to be modified by age, but not race or ethnicity, body mass index, or poverty index ratio. Future studies are needed to track changes in ANA and other autoantibodies before, during, and after exposure to higher levels of triclosan.

These data suggest that exposure to background levels of most xenobiotics are not strongly associated with ANA. More importantly, they provide a conceptual framework for understanding the immunological processes responsible for chemical-induced autoimmune diseases. (TAC)

Citation: Dinse GE, Jusko TA, Whitt IZ, Co CA, Parks CG, Satoh M, Chan EK, Rose KM, Walker NJ, Birnbaum LS, Zeldin DC, Weinberg CR, Miller FW. 2015. Associations between selected xenobiotics and antinuclear antibodies in the National Health and Nutrition Examination Survey, 1999-2004. Environ Health Perspect; doi:10.1289/ehp.1409345 [Online 7 August 2015].

DNA repair can proceed without extensive resection

NIEHS researchers have revealed that extensive DNA resection is not required for recombinational repair of double-strand breaks (DSBs) induced by ionizing radiation (IR). The study helps understand the DNA repair process in both yeast and human cells.

IR, which is commonly used in cancer therapy, induces so called dirty-ended DSBs. For DSBs to be accurately repaired, the breaks must first undergo DNA end resection. As originally hypothesized by co-author Resnick nearly 40 years ago, the process removes a length of the 5’ strand of each DSB end followed by recombination with homologous sequences, preferentially from the sister chromatids. This study is the first to quantitate the impact of resection length on recombinational repair of random dirty DSBs induced by IR.

Using the novel pulse field gel electrophoresis method, which was developed for addressing resected ends, the researchers measured the amount of resection of IR-induced DSBs in yeast with sister chromatids. Compared to wildtype yeast, resection was greatly reduced in strains lacking two enzymes responsible for the extensive resection. However, there was only a small decrease in recombinational repair and cell survival in these strains. Intriguingly, there is little resection of IR-induced DSBs in human cells. The discovery in yeast may imply roles for resection proteins in human DNA repair. (QX)

Citation: Westmoreland JW, Resnick MA. 2015. Recombinational repair of radiation-induced double-strand breaks occurs in the absence of extensive resection. Nucleic Acids Res; doi:10.1093/nar/gkv1109 [Online 25 October 2015].

Pathway responsible for statin-induced type 2 diabetes found

Statins, which are commonly prescribed to lower cholesterol, also prompt the negative side effect of increasing blood glucose levels in humans. Exactly how statin treatment leads to elevated blood sugar remained unknown until NIEHS scientists discovered the molecular mechanism involved in the process. This work may help determine the origins of type 2 diabetes and lead to therapies to treat the disease.

The authors used human liver cells to study how statins alter glucose production, or gluconeogenesis. They found that statin is bound by the drug-sensing transcription factor pregnane X receptor (PXR) within liver cells. This modified PXR scaffolds, or holds in place, protein phosphatase 2C (PP2C), allowing PP2C to dephosphorylate serum/glucocorticoid regulated kinase 2 (SGK2). While bound together, the dephosphorylated SGK2 and PXR translocate to the nucleus and bind to promoters, such as insulin response sequence. This action causes them to upregulate genes important in gluconeogenesis, such as phosphoenolpyruvate carboxykinase 1.

Interestingly, the scientists found that this signal is not present in mice liver cells. As a result, statin treatment in mice suppresses gluconeogenesis. In addition to contributing to the fight against type 2 diabetes, the research demonstrates the necessity of confirming whether scientific data generated in mice applies to humans. (SO)

Citation: Gotoh S, Negishi M. 2015. Statin-activated nuclear receptor PXR promotes SGK2 dephosphorylation by scaffolding PP2C to induce hepatic gluconeogenesis. Sci Rep 5:14076.

Size of uterine fibroids linked with early-life exposure to phytoestrogen

Scientists at NIEHS have observed an association between infant consumption of soy formula and the size of uterine fibroids in African-American women. Previous studies have shown that exogenous hormone exposure during infancy may cause epigenetic changes to the developing body. Soy formula contains phytoestrogens, hormones which can interact with estrogen receptors.

In this cohort study, 1696 African-American women, aged 23-34, underwent ultrasound screening for uterine fibroids, benign tumors of the uterine smooth muscle, and completed a questionnaire about whether they were fed soy formula during infancy. Most participants collected the soy formula data directly from their mothers. The scientists looked at how the prevalence, number, and size of fibroids varied among soy formula-exposed and unexposed participants.

Researchers did not observe an association between consuming soy formula during infancy and the presence of one or more uterine fibroids in adulthood. However, among women who had fibroids, those who had been fed soy formula had larger fibroids than unexposed women, with an approximate 30 percent increase in fibroid diameter and a twofold increase in fibroid volume. The finding lends support to the long-term effects of early-life phytoestrogen exposure. (EM)

Citation: Upson K, Harmon QE, Baird DD. 2015. Soy-based infant formula feeding and ultrasound-detected uterine fibroids among young African-American women with no prior clinical diagnosis of fibroids. Environ Health Perspect; doi:10.1289/ehp.1510082 [Online 13 November 2015].

(Tara Ann Cartwright, Ph.D., is a former postdoctoral fellow in the NIEHS Intracellular Regulation Group. Deacqunita Diggs, Ph.D., is an Oak Ridge Institute for Science and Education fellow in the U.S. Environmental Protection Agency Developmental Toxicity Branch. Emily Mesev is an Intramural Research Training Award (IRTA) postbaccalaureate fellow in the NIEHS Intracellular Regulation Group. Simone Otto, Ph.D., is an IRTA fellow in the NIEHS Ion Channel Physiology Group. Qing Xu is a biologist in the NIEHS Metabolism, Genes, and Environment Group.)