Papers of the Month
By Nancy Lamontagne
Role of BRCA1 in DNA repair
A new study, funded in part by NIEHS, explores the role the gene BRCA1 plays in DNA repair. Because mutations in BRCA1 increase risk of female breast and ovarian cancers, the findings could help researchers design drugs to combat these cancers.
In their normal state, BRCA1 genes produce proteins that repair breaks in DNA and suppress tumor formation. Previous studies showed that the BRCA1 protein joins another tumor suppressor protein known as BARD1 to help form single-stranded DNA during the initial stages of DNA repair. This single-stranded DNA attaches to the protein RAD51, which facilitates the resynthesis of the damaged region of DNA.
To learn more about the role of the BRCA1–BARD1 complex in DNA repair, the researchers developed a new method for expressing BRCA1–BARD1 in insect cells and then purified the complex for biochemical analysis. Using this approach, they found that BRCA1–BARD1 can interact directly with RAD51 to promote the formation of an intermediate that is key for aligning damaged DNA with repair template DNA. The study also found that cells with BRCA1–BARD1 mutants had weakened RAD51 interactions and impaired DNA repair. By identifying a new role for the BRCA1–BARD1 complex in the later stages of DNA repair, the study revealed a potential new target for future cancer therapies.
Zhao W, Steinfeld JB, Liang F, Chen X, Maranon DG, Jian Ma C, Kwon Y, Rao T, Wang W, Sheng C, Song X, Deng Y, Jimenez-Sainz J, Lu L, Jensen RB, Xiong Y, Kupfer GM, Wiese C, Greene EC, Sung P. 2017. BRCA1-BARD1 promotes RAD51-mediated homologous DNA pairing. Nature 550(7676):360–365.
Culturally tailored app shares risks from fish
An NIEHS grantee and colleagues developed and tested a new interactive mobile phone app to communicate fish consumption advice to Native Americans in the upper Great Lakes region. The app — called Gigiigoo'inaan, or “Our Fish” — features custom made digital images to present fish consumption information in an aesthetically pleasing and culturally relevant way.
The app provides personalized recommendations for fish consumption based on data the Chippewa Ottowa Resource Authority gathers about fish contaminants in Native American tribal fisheries in the Great Lakes. After users enter their weight, age, and gender, the software calculates risk and benefit estimates and provides users with a list of fish ranked from most to least beneficial based on the individual’s information. The personalized safe consumption ranges are provided for each fish species.
The researchers partnered with the Inter-Tribal Council of Michigan to pilot test the app for usability, its influence on dietary behavior, and its cultural appropriateness. Focus group participants said they found the general concept and the presentation of the data culturally acceptable and pleasing. Information gathered from the focus groups supported the researchers’ assumption that the tribes desire messaging that promotes stewardship and use of natural resources.
Dellinger MJ, Olson J, Clark R, Pingatore, Ripley MP. 2017. Development and pilot testing of a model to translate risk assessment data for Great Lakes Native American communities using mobile technology. Hum Ecol Risk Assess; doi:10.1080/10807039.2017.1377596 [Online 13 September 2017].
Phthalates link to altered placental function
A new study, funded in part by NIEHS, used human cells to study previously observed relationships between prenatal exposure to phthalates and gene expression essential to placental function. The study provides insight into the molecular basis by which phthalates may alter the function of the placenta.
Researchers have observed links between maternal phthalate exposure and problems during birth and with the health of the child. Studies in animal models and in nonplacental tissue suggested that those links may be associated with effects on placental function. To directly study the effects of phthalates on the human placenta, the scientists used placental cells anonymously donated by women who underwent elective pregnancy terminations. The cells were cultured with metabolites for mono-n-butyl (MnBP), monobenzyl (MBzP), mono-2-ethylhexyl (MEHP), and monoethyl (MEP) phthalates, and a mixture of the phthalate metabolites. They used metabolite concentrations that represented levels previously measured in pregnant women.
Using the human placental cells, the researchers observed that exposure to MnBP, MBzP, and MEHP affected expression of genes essential to placental function in ways previously observed in other studies. Phthalate exposure was also associated with differences in levels of hCG and PPAR gamma. Both proteins are expressed by the affected genes. In some cases, the researchers saw marked, even opposite, differences in hCG protein expression depending on the sex of the cells. The researchers say that these sex differences may be partially regulated by PPAR gamma, a hypothesis that could be further tested to better understand why the hormonal effects of phthalates affect males and females in opposite ways.
Adibi JJ, Zhao Y, Zhan LV, Kapidzic M, Larocque N, Koistinen H, Huhtaniemi IT, Stenman UH. 2017. An investigation of the single and combined phthalate metabolite effects on human chorionic gonadotropin expression in placental cells. Environ Health Perspect 125(10):107010.
Arsenic exposure declines after new EPA regulations
NIEHS grantees reported that after the U.S. Environmental Protection Agency (EPA) lowered the limit for arsenic levels in drinking water, exposure to arsenic dropped significantly among people using public water systems in the U.S. Because arsenic exposure is associated with higher rates of several types of cancer, the researchers estimated that reduced exposure was equivalent to a reduction of 200 to 900 lung and bladder cancer cases or 50 cases of skin cancer per year. They observed no improvements in arsenic exposure rates among users of private wells, which are not federally regulated.
The study used data from 14,127 people in the National Health and Nutrition Examination Survey (NHANES) between 2003 and 2014. The researchers measured levels of dimethylarsinate, the primary metabolite of inorganic arsenic in humans. They examined data from before and after 2006, when EPA lowered the arsenic regulatory limit from 50 to 10 micrograms per liter of drinking water.
After adjusting for other sources of arsenic, such as diet and smoking, the analysis showed that arsenic levels decreased by 17 percent for public water users. Specifically, levels fell from 3.01 micrograms per liter for 2003-2004 to 2.49 micrograms per liter in 2013-2014.
Nigra AE, Sanchez TR, Nachman KE, Harvey DE, Chilled SN, Graziano JH, Navas-Acien A. 2017. The effect of the Environmental Protection Agency maximum contaminant level on arsenic exposure in the USA from 2003 to 2014: an analysis of the National Health and Nutrition Examination Survey (NHANES). Lancet Public Health 2(11)e513−e521.
(Nancy Lamontagne is a science writer with MDB Inc., a contractor for the NIEHS Division of Extramural Research and Training.)