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Environmental Factor, October 2015

Intramural papers of the month

By Robert Brown, Tara Ann Cartwright, Deacqunita Diggs, Shannon Whirledge, and Qing Xu

NTP contributes to the 1000 Genomes High-Throughput Screening Study

National Toxicology Program scientists joined researchers from several institutions to conduct the 1000 Genomes High-Throughput Screening Study, a population-wide in vitro cytotoxicity screening method that provides rapid estimates of human toxicodynamic variability and data on mechanisms that contribute to variation between individuals.

Researchers tested 1,086 lymphoblastoid cell lines (LCLs) from the 1000 Genomes Project, which represented nine populations from five continents, with diverse geographical and ancestral origins, to assess variation in response to 179 chemicals. Various concentrations for each chemical were applied to the LCLs, and approximately half of the chemicals produced a cytotoxic response. Several of these toxic chemicals were shown to associate with a single nucleotide polymorphism, known as rs13120371, in the solute carrier transporter gene SLC7A11. The gene had previously been implicated in chemoresistance, and the findings suggest a major role for membrane proteins and solute carrier transporters in an individual’s susceptibility to environmental chemicals.

This experimental approach can be a model for evaluating individual variability in risk assessment. Although genetic variation accounts for the differences between cell lines, this system can be used to set safety standards for environmental chemicals and determine various mechanisms of toxicity. (DD)

CitationAbdo N, Xia M, Brown CC, Kosyk O, Huang R, Sakamuru S, Zhou YH, Jack JR, Gallins P, Xia K, Li Y, Chiu WA, Motsinger-Reif AA, Austin CP, Tice RR, Rusyn I, Wright FA. 2015. Population-based in vitro hazard and concentration-response assessment of chemicals: the 1000 genomes high-throughput screening study. Environ Health Perspect 123(5):458-466.

Elevated endotoxin in house dust increases the risk of wheeze

In a recent study, NIEHS researchers and collaborators found that elevated levels of bacterial endotoxin in house dust were linked with increased risk of wheeze, and that this exposure was higher in homes with poor living conditions. The findings may provide guidance on how to reduce the number of asthma-related medical visits that result from high endotoxin exposure.  

This research is the largest study of endotoxin exposure to date. The scientists analyzed data for nearly 7,000 participants in the 2005-2006 National Health and Nutrition Examination Survey. Endotoxin levels were measured in dust samples collected from bedding and bedroom floors. Asthma-related outcomes were obtained by interviewing participants using questionnaires. 

The analysis shows that endotoxin exposure is significantly associated with wheeze in the past 12 months, wheeze during exercise, doctor’s office or emergency room visits, and use of prescription drugs for wheeze. Higher endotoxin exposure was linked to lower family income, older homes, carpeted floors, and the presence of cockroaches, pets, younger children, or smokers in the home. The authors propose that reducing poverty and improving living conditions may help alleviate house endotoxin-induced wheeze. (QX)

CitationThorne PS, Mendy A, Metwali N, Salo P, Co C, Jaramillo R, Rose KM, Zeldin DC.2015. Endotoxin exposure: predictors and prevalence of associated asthma outcomes in the U.S. Am J Respir Crit Care Med; doi:10.1164/rccm.201502-0251OC [Online 10 August 2015].

Enzyme responsible for majority of mutations in certain cancers identified

Scientists were aware that the apolipoprotein B mRNA editing enzyme catalytic polypeptide-like (APOBEC) cytidine deaminases were capable of inducing DNA damage and mutations, but a team led by NIEHS researchers determined that mutations made by APOBEC3A were more frequently found in certain cancers. Other researchers previously named APOBEC3B as the deaminase primarily responsible for a majority of DNA mutations in cancerous cells. The study may help scientists further determine the mechanism of genome instability in cancer. 

APOBEC3A and APOBEC3B prefer distinct DNA motifs, which allowed the researchers to follow their signatures in The Cancer Genome Atlas, a cancer sequence database. The authors mined 15 recently published cohorts of cancer whole-genome mutations and found that five cancer types — bladder, breast, head and neck, lung adenocarcinoma, and lung squamous cell carcinoma — had a significant presence of APOBEC signatures. In these cancers, APOBEC3A caused 10 times more DNA sequence changes than APOBEC3B. These distinct signatures may prove useful when determining the course of treatment for patients, while the presence or absence of either mutagen may be useful for cancer screening. (SW)

CitationChan K, Roberts SA, Klimczak LJ, Sterling JF, Saini N, Malc EP, Kim J, Kwiatkowski DJ, Fargo DC, Mieczkowski PA, Getz G, Gordenin DA. 2015. An APOBEC3A hypermutation signature is distinguishable from the signature of background mutagenesis by APOBEC3B in human cancers. Nat Genet 47(9):1067-1072. (Story)

Prenatal arsenic exposure induces early onset of puberty and obesity in CD-1 mice

NIEHS researchers have investigated the impact of prenatal exposure to arsenic at two levels — the U.S. Environmental Protection Agency drinking water standard of 10 parts per billion and the tumor-inducing level of 42.5 parts per million — on reproductive and metabolic functions. Female CD-1 mice were exposed in utero via drinking water during the second half of gestation, which was between 10 days after fertilization and birth, and monitored through adulthood. 

The study demonstrated that CD-1 females exposed to arsenic in utero exhibited early onset puberty. Females in the 42.5 parts per million treatment group had fewer litters and a shorter fertile period compared to the 10 parts per billion treatment group. Both arsenic-exposed groups also exhibited higher body weight and fat content. In addition to increasing the incidence of obesity, exposure to arsenic also impaired glucose tolerance.

Taken together, these data suggest that arsenic-induced weight gain, glucose intolerance, and early onset puberty could derive from epigenetic changes as a consequence of in utero exposure. These epigenetic changes can occur at cellular or systemic levels, influencing metabolism and hormone production. Future studies are needed to shed light on the mechanism underlying arsenic-associated complications and are of foremost importance to understanding the possible health outcomes in humans. (TAC)

CitationRodriguez KF, Ungewitter EK, Crespo-Mejias Y, Liu C, Nicol B, Kissling GE, Yao HH-C. 2015. Effects of in utero exposure to arsenic during the second half of gestation on reproductive end points and metabolic parameters in female CD-1 mice. Environ Health Perspect; doi:10.1289/ehp.1509703 [Online 21 August 2015]. (Story)

Crystallography reveals new mechanism of action for polymerase mu

NIEHS researchers discovered a novel aspect of the DNA repair mechanism for polymerase mu (Pol mu) utilized in the repair of double strand DNA breaks.

Researchers determined X-ray crystal structures of Pol mu with a 2-nucleotide gapped DNA substrate and an incoming nucleotide, to clarify the steps involved in its catalytic DNA strand break repair cycle. Scientists found that Pol mu uses the last unpaired template base on the 5ʹ end of the DNA break to direct nucleotide binding and incorporation. This mechanism of action is in stark contrast to the canonical mechanism described for other template-dependent DNA polymerases, which involves using the first available 3ʹ template base to direct strand elongation.

This report highlights the importance of understanding the structure and function relationships of this polymerase and provides critical insights into its behavior within the context of DNA strand break repair. (RB)

CitationMoon AF, Gosavi RA, Kunkel TA, Pedersen LC, Bebenek K. 2015. Creative template-dependent synthesis by human polymerase mu. Proc Natl Acad Sci U S A 112(33):E4530-E4536.

(Robert Brown, Ph.D., is an Intramural Research and Training Award (IRTA) fellow in the NIEHS Cell Biology Group. Tara Ann Cartwright, Ph.D., is a former postdoctoral fellow in the NIEHS Intracellular Regulation Group. Deacqunita Diggs, Ph.D., is a National Health and Environmental Effects Laboratory fellow in the U.S. Environmental Protection Agency Developmental Toxicity Branch. Shannon Whirledge, Ph.D., is an IRTA fellow in the NIEHS Molecular Endocrinology Group. Qing Xu is a biologist in the NIEHS Metabolism, Genes, and Environment Group.)

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