Leveraging class-based methods to predict chemical toxicity

A recent commentary by researchers from the Division of Translational Toxicology promotes a better understanding of clustering and classification approaches (CCAs) in toxicity research and risk assessment, and advocates for increased use within international collaborations.

The field of toxicology has witnessed substantial advancements in recent years, particularly with the adoption of new methodologies to understand and predict chemical toxicity. In particular, class-based methods such as CCAs help scientists understand hazard and risk concerns associated with groups of chemicals without additional laboratory work. However, due to their intricacy, deep understanding and careful selection are imperative to align the adequate methods with their intended applications.

In the new commentary, the authors set out to deepen the understanding of class-based approaches by elucidating the pivotal role of chemical similarity (structural and biological) in CCAs. According to the authors, one important take-home message is that the effectiveness of these approaches depends on the right definition and measure of similarity, which varies based on context and objectives of the study. They distinguish between end point–agnostic similarity, used in unsupervised methods for exploratory analysis with general features, and end point–specific similarity, used in supervised methods for predictive modeling based on specific outcomes. Unsupervised methods help in generating hypotheses, whereas supervised methods focus on creating models based on particular biological or toxicological responses.

This choice between the two types is influenced by how chemical structures are represented and the respective labels that indicate biological activity. Another key take-home message is that interdisciplinary collaboration and implementation of recommendations presented in the commentary could play an important role in enhancing the use of CCAs across diverse fields. (JW)

Citation: Mansouri K, Taylor K, Auerbach S, Ferguson S, Frawley R, Hsieh JH, Jahnke G, Kleinstreuer N, Mehta S, Moreira-Filho JT, Parham F, Rider C, Rooney AA, Wang A, Sutherland V. 2024. Unlocking the potential of clustering and classification approaches: navigating supervised and unsupervised chemical similarity. Environ Health Perspect 132(8):85002.

How a protein called Pms1 affects genome stability

Instability throughout the yeast genome can be caused by defective activity of a protein called Pms1, according to NIEHS researchers and their collaborators.

In most bacteria and eukaryotes, which are cells with a nucleus and membrane-bound organelles, mismatches made during DNA replication are corrected by DNA mismatch repair. Inactivation of this repair pathway strongly increases mutation rates, which can affect evolution and have several adverse consequences. Pms1’s endonuclease activity directs mismatch repair by generating a nick in the newly replicated DNA strand. Inactivating Pms2, the human homologue of yeast Pms1, is known to increase colorectal and uterine cancer risk.

The researchers used whole genome sequencing to show that loss of Pms1 endonuclease activity results in strong mutator effects throughout the Saccharomyces cerevisiae (budding yeast) genome. Mutation rates were strongly increased for mutations resulting from all types of single-base substitutions and for a wide variety of single- and multi-base indel mutations.

Additional results revealed similarity in the rates and specificity of mutagenesis due to loss of Msh2 and Pms1 endonuclease, implying that these two proteins act similarly to reduce mismatch rates. According to the authors, the results are consistent with studies demonstrating that endonuclease activity in the PMS1 gene in budding yeast is critical for DNA mismatch repair. (JW)

Citation: Lujan SA, Garbacz MA, Liberti SE, Burkholder AB, Kunkel TA. 2024. Instability throughout the Saccharomyces cerevisiae genome resulting from Pms1 endonuclease deficiency. Nucleic Acids Res gkae616.

Microbes in house dust may affect lung function

State-of-the-art metagenomic sequencing has revealed specific microorganisms in indoor dust related to pulmonary function and airway inflammation, according to NIEHS researchers and their collaborators.

Respiratory health can be affected by chronic exposure to microorganisms inside homes; however, few studies have used advanced sequencing methods to examine adult respiratory outcomes. In the new study, the researchers aimed to identify metagenomic profiles in house dust related to pulmonary function and airway inflammation in adults. Using whole metagenome shotgun sequencing, they characterized 1,264 microbial species in vacuumed bedroom dust from 779 homes in the United States.

Although overall microbial diversity was not significantly related to pulmonary function, many individual microbial genera, which are groups of species, were differentially abundant in relation to pulmonary function or airway inflammation. Among the genera related to pulmonary function, several were previously linked to lung diseases. The results suggest that chronic exposure to specific microorganisms indoors may play a role in respiratory outcomes.

According to the authors, further investigation of the genera identified could reveal how exposure to indoor microorganisms contributes to respiratory health. Moreover, this comprehensive investigation of microbial signatures in house dust and adult respiratory outcomes could help elucidate complex mechanisms of chronic exposure to house dust and respiratory health across the life course. (JW)

Citation: Lee M, Kaul A, Ward JM, Zhu Q, Richards M, Wang Z, González A, Parks CG, Beane Freeman LE, Umbach DM, Motsinger-Reif AA, Knight R, London SJ. 2024. House dust metagenome and pulmonary function in a US farming population. Microbiome 12(1):129.

Prenatal organophosphate ester exposure may affect fetal development

Exposure to organophosphate esters (OPEs) during pregnancy may be linked to an increased risk of developmental toxicity, according to NIEHS researchers and their collaborators.

OPEs are chemicals used as flame retardants and plasticizers in a variety of consumer products (e.g., furniture, textiles). Various studies have reported that continuous exposure to OPEs may adversely affect reproductive health and birth outcomes. Although previous animal studies have revealed developmental toxicity due to OPE exposure, evidence in human studies has been limited and inconclusive.

To address this knowledge gap, the researchers examined the link between prenatal exposure to OPE flame retardants and plasticizers and fetal growth. Their analysis involved 900 participants from the LIFECODES Fetal Growth Study (2008-2018), an enriched case-cohort for babies born at the small and large ends of the growth spectrum. The authors evaluated the levels of urinary OPE biomarkers and used both ultrasound and delivery measures to assess fetal growth.

The researchers found a strong and consistent association between prenatal OPE exposures and an increase in fetal growth during pregnancy. However, these associations were not significant at the time of delivery. One OPE biomarker named diphenyl phosphate (DPHP) was associated with an increased risk of babies being born small for gestational age.

Together, the results provide new evidence indicating that OPE exposure during pregnancy may affect fetal growth and development. According to the authors, this work demonstrates a possible effect of prenatal OPE exposure on a baby’s development that could potentially involve downstream consequences across the life span. (SS)

Citation: Bommarito PA, Stevens DR, Welch BM, Ospina M, Calafat AM, Meeker JD, Cantonwine DE, McElrath TF, Ferguson KK. 2024. Organophosphate ester flame retardants and plasticizers in relation to fetal growth in the LIFECODES Fetal Growth Study. Environ Health Perspect 132(7):77001.

Early-life pesticide exposure associated with higher IBD incidence

Exposure to pesticides during childhood and adolescence may increase the incidence of inflammatory bowel disease (IBD), according to NIEHS researchers.

IBD is an autoimmune disease characterized by chronic intestinal inflammation and includes Crohn’s disease and ulcerative colitis. There are few known risk factors for the disease. Use of specific pesticides was associated with higher IBD incidence among farmers, but no study has examined the effects of pesticide exposure in early life.

The researchers evaluated pesticide use during childhood and adolescence and IBD incidence among 48,382 U.S. women ages 35-74 at enrollment in the Sister Study. They identified 277 incident IBD cases and found women whose long-term childhood residence was regularly treated with pesticides were 1.26 times as likely to be diagnosed with IBD than those without exposure. The risk estimates were higher for those who personally applied pesticides.

The study team also found a positive association between IBD and exposure to pesticides sprayed from a truck or airplane before DDT was banned in 1975. In addition, those who lived on farms and reported being in the fields during pesticide use were approximately twice as likely to develop IBD as those who were not exposed.

According to the researchers, the findings contribute to a small but growing body of evidence indicating pesticide exposure is a contributor to IBD development. In addition, the study establishes childhood and adolescence as a potential window of susceptibility. Practices that reduce pesticide exposure during early life may help reduce the burden of IBD. (DM)

Citation: Chen D, Woo JMP, Parks CG, Lawrence KG, O’Brien KM, Sandler RS, Sandler DP. 2024. Childhood and adolescent residential and farm pesticide exposures and inflammatory bowel disease incidence in a U.S. cohort of women. Sci Total Environ (946)174475.