Papers of the Month
Intramural
By Janelle Weaver and Shruti Somai
Making it easy to explore chemical datasets
A new chemical grouping workflow is user-friendly and accessible to researchers who do not have extensive programming skills, according to researchers from the Division of Translational Toxicology.
Over recent decades, substantial data for chemicals have been generated. One type of method for analyzing this data is chemical grouping, or categorizing compounds based on shared characteristics. This process allows researchers to conduct safety and risk assessments and to prioritize chemicals for testing. Sharing methods such as chemical grouping is crucial, but open-source tools often lack documentation and require significant programming skills for setup and use.
To overcome these limitations, the researchers used machine-learning methods to develop a user-friendly chemical grouping workflow. This automated workflow, part of the Modeling and Visualization Pipeline (MoVIZ), was designed to democratize chemical grouping methods for nonexperts and simplify their application for the community. It was developed on a free, open-source, data analytics platform called Konstanz Information Miner (KNIME), is available for download via the GitHub or KNIME Community Hub, and is accessible as a web application via the KNIME Server WebPortal.
According to the authors, their approach provides a valuable tool for chemists and researchers to analyze chemical datasets, gain insights into chemical properties, and facilitate decision making for drug discovery and chemical risk assessment. (JW)
Citation: Moreira-Filho JT, Ranganath D, Conway M, Schmitt C, Kleinstreuer N, Mansouri K. 2024. Democratizing cheminformatics: interpretable chemical grouping using an automated KNIME workflow. J Cheminform 16(1):101.
Supporting genome stability by sealing nicks
A molecule called DNA ligase 1 (LIG1) plays an important role in determining the rate of certain mutations across the yeast genome, according to NIEHS researchers and their collaborators.
DNA ligation is a molecular biology process in which two DNA fragments are joined together to form a single strand. LIG1 is an enzyme that catalyzes ligation events during DNA replication and repair. Specifically, this molecule finalizes DNA replication in the nucleus by accurately sealing nicks.
In the new study, the researchers used a LIG1 variant, which does not catalyze accurate ligation events, to study mutation in the yeast genome. They focused on single-base insertions, which occur when one base pair is added to a DNA sequence. The results revealed that the LIG1 variant led to a strong increase in single base addition rates across the nuclear genome.
The findings highlight the importance of highly efficient and accurate DNA ligation to prevent single base insertions and to enhance genome stability. Understanding this process may be important from a clinical standpoint, given that mutations leading to LIG1 deficiency can result in immune disorders and increased sensitivity to DNA-damaging agents. (JW)
Citation: Williams JS, Lujan SA, Arana ME, Burkholder AB, Tumbale PP, Williams RS, Kunkel TA. 2024. High fidelity DNA ligation prevents single base insertions in the yeast genome. Nat Commun 15(1):8730.
Prenatal pesticide exposure may affect pediatric heart health
Prenatal organophosphate exposure may increase the risk of cardiovascular diseases in children, according to NIEHS researchers and their collaborators.
Organophosphate pesticides are historically one of the most widely used insecticides in agriculture and household applications. Although acute high-dose exposure can be extremely toxic, most individuals are exposed to low and chronic doses of organophosphate pesticides. Studies have reported that low-dose chronic organophosphate pesticide exposures disrupt critical cardiometabolic pathways resulting in a broad spectrum of diseases. Although it is well understood that prenatal organophosphate pesticide exposure impairs fetal development, the effects on long-term health outcomes, particularly pediatric cardiovascular health, remain understudied.
To address this knowledge gap, the researchers examined the link between prenatal organophosphate pesticide exposure and cardiovascular outcomes in children. Their analysis involved 643 children born between 2002 and 2006, whose parents enrolled in the Generation R Study, a prospective cohort in Rotterdam, Netherlands. The authors evaluated urinary concentrations of six organophosphate pesticide metabolites from pregnant participants and performed cardiovascular measurements on their children. The findings showed that children containing mutations in the PON1 gene, a gene corresponding to the enzyme paraoxonase responsible for organophosphate pesticide detoxification in the body, had an increased risk of developing adverse vascular and glycemic outcomes for increases in prenatal organophosphate concentrations.
Together, the results provide new evidence indicating that organophosphate pesticide exposure during pregnancy may affect the cardiovascular health of children. According to the authors, further research is warranted to assess long-term health effects of organophosphate pesticide exposure, especially in children containing PON1 mutations. (SS)
Citation: Stevens DR, Blaauwendraad SM, Bommarito PA, van den Dries M, Trasande L, Spaan S, Pronk A, Tiemeier H, Gaillard R, Jaddoe VWV, Ferguson KK. 2024. Gestational organophosphate pesticide exposure and childhood cardiovascular outcomes. Environ Int 193:109082.
Air pollution exposure may be linked to ovarian cancer
Greater levels of ambient nitrogen dioxide may be associated with a higher incidence of ovarian cancer, according to NIEHS researchers and their collaborators.
Outdoor air pollution is classified as a carcinogen based primarily on evidence of associations with lung cancer. It has increasingly been linked to higher rates of other cancers, yet there has been relatively little research on ovarian cancer, which is the deadliest and the second-most common gynecologic cancer in the United States.
The new study expands upon the existing literature by investigating the relationship between individual-level residential estimates of air pollution and the incidence of ovarian cancer in a large, nationwide sample of 40,308 women. The results revealed that higher rates of ovarian cancer was associated with greater concentrations of ambient nitrogen dioxide, but not particulate matter or ozone. However, the findings suggest that the potential link between exposure to particulate matter and ovarian cancer could vary by geographic region, possibly due to different emission sources.
Overall, the results are consistent with growing evidence for a relationship between air pollution and hormone-dependent female cancers. According to the authors, the study suggests that exposure to nitrogen dioxide, which is considered a proxy for traffic-related emissions, may be a risk factor for ovarian cancer, but more research is needed to fully understand the underlying biological mechanisms. (SS)
Citation: Ish JL, Chang CJ, Bookwalter DB, Jones RR, O'Brien KM, Kaufman JD, Sandler DP, White AJ. 2024. Outdoor air pollution exposure and ovarian cancer incidence in a United States-wide prospective cohort study. Environ Health Perspect 132(10):107701.
Why girls worldwide are experiencing earlier puberty
Environmental compounds may trigger early female puberty by activating the kisspeptin receptor (KISS1R) or GnRH receptor (GnRHR) in a brain region called the hypothalamus, according to NIEHS researchers and their collaborators at the National Center for Advancing Translational Sciences and Northwestern University.
Earlier puberty is associated with an increased risk of psychosocial problems, obesity, diabetes, cardiovascular disease, and breast cancer. There has been an alarming global trend toward earlier breast development in girls over the past decade, but an environmental trigger has yet to be convincingly identified.
With this goal in mind, the researchers used a quantitative high-throughput screening approach to identify relevant environmental compounds, focusing on the hypothalamus — the gland that controls puberty. They screened approximately 10,000 compounds, including licensed pharmaceuticals and environmental chemicals, and conducted experiments in various cell types, including human hypothalamic neurons, and in developing zebrafish larvae.
The results revealed novel compounds that can bind to and activate the GnRHR or KISS1R, and therefore may contribute to the trend in earlier puberty in girls. In particular, the researchers identified musk ambrette as a compound that can stimulate these receptors. Given the environmental persistence and continued use of musk chemicals, they should be further investigated in future epidemiological studies of pubertal timing. (JW)
Citation: Yang S, Zhang L, Khan K, Travers J, Huang R, Jovanovic VM, Veeramachaneni R, Sakamuru S, Tristan CA, Davis EE, Klumpp-Thomas C, Witt KL, Simeonov A, Shaw ND, Xia M. 2024. Identification of environmental compounds that may trigger early female puberty by activating human GnRHR and KISS1R. Endocrinology 165(10):bqae103.
(Janelle Weaver, Ph.D., is a contract writer for the NIEHS Office of Communications and Public Liaison. Shruti Somai, Ph.D., is a visiting fellow in the Genome Integrity and Structural Biology Laboratory.)
