Papers of the Month
By Nicholas Alagna, Mimi Huang, Florencia Pascual, Victoria Placentra, and Qing Xu
Pesticides identified for possible cancer hazard reviews
Researchers in the Division of the National Toxicology Program (DNTP) successfully employed a two-tiered method for identifying and prioritizing candidate pesticides for possible cancer hazard assessments. Their approach included an initial search for registered pesticides that were classified according to the U.S. Environmental Protection Agency (EPA) as possible, suggestive, or likely human carcinogens. They also searched for pesticides that were widely used and had not undergone a hazard assessment in the past five years. Using the EPA database and available resources, the researchers found a total of 18 pesticides that met these requirements.
In the second part of their process, the investigators conducted a literature search, screen, and evidence mapping of cancer epidemiology studies with pesticide-specific data on the 18 compounds. These studies were also published after each pesticide’s last EPA carcinogenicity assessment. The scientists found that for 16 of the 18 pesticides, human cancers data had been published after the initial carcinogenicity evaluation. Of these 16, eight had three or more studies published on at least one type of cancer. This protocol could serve as a tool for identifying pesticides that could potentially cause cancer. (NA)
Citation: Schwingl PJ, Lunn RM, Mehta SS. 2021. A tiered approach to prioritizing registered pesticides for potential cancer hazard evaluations: implications for decision making. Environ Health 20(1):13.
DNA ligase 1 mutations offer clues to LIG1 syndrome
NIEHS researchers and collaborators revealed how mutations of human DNA ligase 1 (LIG1), a DNA joining enzyme, can change its structure and reduce its activity. These changes possibly lead to the development of immunological diseases. The findings shed light on the molecular mechanisms underlying LIG1 syndrome, as well as potential new strategies to manage the disease.
DNA ligases catalyze the joining of two pieces of DNA, using the magnesium ion as an essential cofactor. Human LIG1 has critical roles in DNA replication, recombination, and repair. LIG1 mutations have been found in patients with LIG1 syndrome, clinically manifested as immunodeficiency and hypersensitivity to DNA-damaging agents. In this study, the researchers investigated the structural and biochemical impacts of two mutations identified in LIG1 syndrome, namely R641L and R771W.
Through analysis of high-resolution X-ray structures, the researchers discovered a cooperative network of LIG1-DNA-magnesium interactions that are required for efficient ligation. LIG1 mutants R641L and R771W disrupted this network, compromised the binding of magnesium, and decreased ligation efficiency. Interestingly, the compromised LIG1 activity caused by the mutations could be partially resolved by adding magnesium. This finding suggests supplementing one’s diet with magnesium could treat LIG1 syndrome. (QX)
Citation: Jurkiw TJ, Tumbale PP, Schellenberg MJ, Cunningham-Rundles C, Williams RS, O'Brien PJ. 2021. LIG1 syndrome mutations remodel a cooperative network of ligand binding interactions to compromise ligation efficiency. Nucleic Acids Res 49(3):1619–1630.
Regional air pollution’s effects on Black women’s breast cancer risk
NIEHS researchers and collaborators did not find evidence to support an association between air pollution and breast cancer risk, except among women living in the Midwestern United States.
Air pollution, a complex mixture of carcinogens and endocrine disruptors, has been associated in past studies with breast cancer risk. Since previous research was conducted mostly in white women, more work is needed to assess the impact in women of color. Black women may be exposed to higher levels and different types of pollutants and are more likely to be diagnosed with tumor subtypes that do not respond to treatment.
In 41,317 women participating in the Black Women’s Health Study, the investigators evaluated whether higher residential levels of particulate matter less than 2.5 micrometers in size (PM2.5), nitrogen dioxide (NO2), and ozone (O3) was associated with higher breast cancer incidence. The scientists did not find evidence of higher risk for NO2 or O3, but they observed PM2.5 was associated with higher risk of breast cancer among women living in the Midwest. PM2.5 is heterogenous and varies geographically. The researchers suggested that the composition of PM2.5 in the Midwest may reflect regional industrial emissions. These findings highlight the need to understand how regional differences and individual compounds influence cancer risk. (FP)
Citation: White AJ, Gregoire AM, Niehoff NM, Bertrand KA, Palmer JR, Coogan PF, Bethea TN. 2020. Air pollution and breast cancer risk in the Black Women's Health Study. Environ Res 194:110651.
Epoxide hydrolase 3 required to maintain skin structure
NIEHS researchers and their collaborators were the first to demonstrate a role for epoxide hydrolase 3 (EPHX3) in skin barrier function in vivo. Scientists disrupted the EPHX3 gene in mice, creating a knockout strain. In this population, a process called ceramide linoleate epoxide hydrolysis was reduced. This reduction impaired the skin’s barrier function and increased water evaporation.
EPHX3 belongs to a family of enzymes that break down compounds containing an epoxide residue. In humans, EPHX3 has activity in several tissues including the skin. Compounds like ceramides and linoleate are important for maintaining the skin barrier and retaining moisture. When these compounds are not properly metabolized, skin barrier function is impaired, which is associated with dry skin conditions like ichthyosis and psoriasis.
The researchers knocked out the gene that encodes EPHX3 in mice, and then analyzed blood plasma and skin by liquid chromatography-mass spectrometry (LC-MS) to detect levels of EPHX3 substrates. The EPHX3-deficient mice showed no difference in fatty acid epoxide hydrolysis but had fewer hydrolyzed ceramides and fewer total ceramides in the epidermis, which resulted in higher trans epidermal water loss. (VP)
Citation: Edin ML, Yamanashi H, Boeglin WE, Graves JP, DeGraff LM, Lih FB, Zeldin DC, Brash AR. 2020. Epoxide hydrolase 3 (Ephx3) gene disruption reduces ceramide linoleate epoxide hydrolysis and impairs skin barrier function. J Biol Chem 296:100198.
Metformin may reduce risk of certain breast cancers
According to a team led by NIEHS researchers, although women with type 2 diabetes (T2D) may have increased breast cancer risk, use of the antidiabetic drug metformin may reduce that risk. Women with T2D and long-term metformin use were 38% less likely to develop estrogen receptor-positive (ER-positive) breast cancer compared to women without T2D. However, women with T2D and metformin use were at increased risk of ER-negative breast cancer and triple-negative breast cancer (TNBC).
The scientists used data from 44,541 women in the Sister Study, a prospective study of risk factors for breast cancer and other diseases. Participants were aged 35-74 years and breast-cancer free at enrollment. The volunteers reported on physician-diagnosed T2D and completed annual follow up questionnaires.
Associations between T2D or metformin and breast cancer varied by breast cancer subtype. While the researchers did not find an association between T2D and breast cancer overall, 74% of those with T2D used metformin and long-term metformin treatment was associated with reduced risk of ER-positive breast cancer. The increased risk for ER-negative breast cancer and TNBC suggests that metformin does not protect against these breast cancer subtypes, perhaps due to differences in how subtypes of breast cancer develop. (MH)
Citation: Park Y-MM, Bookwalter DB, O'Brien KM, Jackson CL, Weinberg CR, Sandler DP. 2021. A prospective study of type 2 diabetes, metformin use, and risk of breast cancer. Ann Oncol 32(3):351–359.
(Nicholas Alagna is an Intramural Research Training Award [IRTA] postbaccalaureate fellow in the NIEHS Mechanisms of Mutation Group. Mimi Huang, Ph.D., is an IRTA fellow in the DNTP Systems Toxicology Group. Florencia Pascual, Ph.D., is a scientist in the NIEHS Pediatric Neuroendocrinology Group. Victoria Placentra is an IRTA postbaccalaureate fellow in the NIEHS Mutagenesis and DNA Repair Regulation Group. Qing Xu is a biologist in the NIEHS Metabolism, Genes, and Environment Group.)