Papers of the Month
By Janelle Weaver and Meklit Daniel
Researchers introduce flexible data analysis tool to broader scientific community
An open-source computational platform called ToxicR could empower scientists to break free from a one-size-fits-all modeling approach to illuminate the effects of potentially harmful chemicals on biological processes, according to NIEHS researchers and their collaborators.
The development of high-throughput bioassays to understand cellular and molecular responses to chemical exposures has exploded over the past 15 years. To analyze the large amounts of data produced by these assays, scientists use various computational and data analytic tools. Yet existing software is frequently based on workflows built from assumptions that may not be optimal for novel research questions.
To address this problem, the NIEHS Biostatistics and Computational Biology Branch, in cooperation with the National Toxicology Program (NTP) and U.S. Environmental Protection Agency (EPA), developed ToxicR. This computational platform implements standard analyses used by NTP and EPA, as well as standard tests NTP uses in rodent toxicology studies. However, it allows modifications of these approaches based upon researchers' needs, which ensures transparency, reproducibility, and confidence when developing analysis pipelines.
The goal is to allow access to state-of-the-art methods for dose–response and high-throughput analyses so that researchers can create novel analysis pipelines that are fit for purpose. The unique features of ToxicR will allow researchers in other fields to add modules, increasing its functionality in the future to greatly facilitate the process of scientific discovery.
Citation: Wheeler MW, Lim S, House JS, Shockley KR, Bailer AJ, Fostel J, Yang L, Talley D, Raghuraman A, Gift JS, Davis J Allen, Auerbach SS, Motsinger-Reif AA. 2023. ToxicR: a computational platform in R for computational toxicology and dose–response analyses. Computat Toxicol 25:100259. (JW)
Soy formula may increase risk of benign uterine tumors
The consumption of soy-based formula during infancy could elevate the risk of developing fibroids in adulthood, according to NIEHS researchers and their collaborators.
Uterine fibroids are highly prevalent, non-cancerous tumors that disproportionately affect Black women. Soy formula feeding during infancy has been linked to uterine fibroids in adulthood, but studies are few, and they rely on self-report of both soy formula use and fibroid diagnosis. Soy-based infant formula contains phytoestrogens, which are plant-derived compounds that have documented estrogenic activity in vaginal tissue of infant girls. Early-life phytoestrogen treatment in rodents results in altered development of the entire reproductive tract. Yet the risk of adverse health outcomes later in life in humans are not well understood, nor are they factored into current recommendations.
The researchers examined the relationship between soy formula feeding in infancy and fibroid development in adulthood among 1,610 self-identified Black/African-American women between the ages of 23 and 35 years at enrollment in the Study of Environment, Lifestyle and Fibroids. When possible, they gathered soy formula data from the participants’ mothers (89% of sample). They conducted standardized ultrasound examinations during four clinic visits over five years, a study design that provides the most accurate data on fibroid incidence to date.
Results showed that participants fed soy formula within two months of birth and for greater than six months had an estimated 56% increase in fibroid incidence compared with those never fed soy formula. The authors noted that early infancy is a time when there is transient activation of the hypothalamic-pituitary-gonadal axis, and this might be a particularly susceptible window for exogenous estrogen exposure.
Citation: Langton CR, Harmon QE, Upson K, Baird DD. 2023. Soy-based infant formula feeding and uterine fibroid development in a prospective ultrasound study of Black/African-American women. Environ Health Perspect 131(1):17006. (JW)
Urine biomarkers may hold promise for patients with muscle diseases
An optimized urine proteomics workflow revealed proteins associated with key features of juvenile dermatomyositis (JDM), according to NIEHS researchers and their collaborators.
Myositis is a rare and debilitating autoimmune disease that results in chronic muscle inflammation and weakness. One particularly rare and complex subtype is JDM, which manifests in childhood. Because there are currently only a few sensitive and reliable biomarkers, there is a clear and urgent need for the development of noninvasive methods for determining prognosis and responses to treatment. Specifically, the discovery and validation of sensitive and specific urinary biomarkers will help fill a critical void in the myositis field.
To address this need, the researchers used mass spectrometry-based proteomics to analyze urine samples from 20 patients with JDM and 21 healthy control subjects. The results showed that Cathepsin D and Galectin-3 binding protein were significantly increased in the urine of patients with JDM, consistent with previous findings. These results were confirmed with ELISA tests. In addition, Cathepsin D was associated with myositis disease activity and damage measures.
The researchers also identified novel JDM candidate biomarkers related to key aspects of myositis. According to the authors, these results support the use of urine proteomics for the development of a panel of biomarkers to assist in prognosis and targeted treatment.
Citation: Morales M, Alayi TD, Tawalbeh SM, Sydenstricker AV, Spathis R, Kim H, Nagaraju K, Hathout Y, Rider LG. 2023. Urine proteomics by mass spectrometry identifies proteins involved in key pathogenic pathways in patients with juvenile dermatomyositis. Rheumatology kead033. (JW)
Neighborhood disadvantage may increase risk of immune-related illness
Living in a disadvantaged neighborhood may increase risk for pneumonia and frequent colds, according to NIEHS researchers.
Immune-related illnesses are a major global health burden. Neighborhood disadvantage has been linked with pneumonia and influenza-associated hospitalizations, but previous studies considered one outcome at a time. Further, definitions of neighborhood disadvantage differ across the literature, and researchers generally use data at the census tract level (covering as many as 8,000 people).
Instead, the NIEHS team used a comprehensive index (the Area Deprivation Index) representing 17 U.S. Census poverty, education, housing, and employment indicators to rank neighborhood disadvantage across the country at the census-block group level (as few as 250 households). The researchers sought to explore the potential association between neighborhood disadvantage and immune-related conditions, including any or frequent colds; any or frequent flu; cold sores; pneumonia; shingles; and an aggregated outcome. Data on illnesses were self-reported by 10,543 participants in the NIEHS Gulf Long-term Follow-up (GuLF) Study.
The researchers found that compared with those living in the least-deprived neighborhoods, participants living in neighborhoods with greater levels of disadvantage were more likely to have had pneumonia and frequent colds. The authors recommend longitudinal studies using more robust immune-related illness measures to clarify these relationships.
Citation: Patel OP, Lawrence KG, Parks CG, Bodkin M, Jackson III WB, Engel LS, Sandler DP. 2023. Neighborhood disadvantage and immune-related illnesses among residents living in the US Gulf States. Ann Epidemiol 78:44–46. (MD)
Advanced molecular profiling sheds new light on mammalian biology
A technical advance has provided a more sophisticated picture of signaling molecules called inositol phosphates (InsPs) and pyrophosphates (PP-InsPs), according to NIEHS researchers and their collaborators.
InsPs and PP-InsPs play wide-ranging biological roles in mammals. Yet technical challenges have prevented a complete profiling of the levels of these molecules in various tissues. To achieve this goal, the researchers applied a method called capillary electrophoresis mass spectrometry (CE-MS) to mouse tissues.
The colon was found to contain unusually high levels of InsPs and PP-InsPs, including two unexpected chemical species (called 4/6-PP-InsP5 and 2-PP-InsP5) that have not previously been described in any animal cell. The enzymes that synthesize these new molecules remain to be identified. Taken together, the results indicate that the cellular metabolism and the biological significance of PP-InsPs is far more complex than previously thought.
Moreover, the CE-MS method was sensitive enough to enable first-time measurements of PP-InsPs from patient samples such as colon biopsies and blood cells, which contained 4/6-PP-InsP5 and 2-PP-InsP5. With the ability to profile PP-InsPs from human biopsies and blood samples, their establishment as potential disease biomarkers will become an important future endeavor.
Citation: Qiu D, Gu C, Liu G, Ritter K, Eisenbeis VB, Bittner T, Gruzdev A, Seidel L, Bengsch B, Shears SB, Jessen HJ. 2022. Capillary electrophoresis mass spectrometry identifies new isomers of inositol pyrophosphates in mammalian tissues. Chem Sci 14(3):658–667. (JW)
(Janelle Weaver, Ph.D., is a contract writer for the NIEHS Office of Communications and Public Liaison, and Meklit Daniel is a fellow in the NIEHS Environment and Cancer Epidemiology Group.)