Papers of the Month
Intramural
By Janelle Weaver, Shruti Somai, and Meklit Daniel
Flame retardants may affect the developing immune system
Exposure to a flame retardant called tris(chloropropyl) phosphate (TCPP) during rats' early life and development inhibits the immune response of antibody-forming cells, according to researchers from the NIEHS Division of Translational Toxicology.
TCPP is an organophosphate flame retardant (OPFR) used in construction materials and consumer products. TCPP is often used as a replacement for brominated flame retardants, which have been banned or voluntarily phased out in many countries due to their potential adverse health effects. Although there is some evidence OPFRs may disrupt biological processes involved in development and reproduction, no studies have previously investigated the immune effects of developmental exposures to this class of chemicals.
In this study, researchers assessed how TCPP exposure in a rat model affected developing immune systems. They found oral exposure to TCPP from early life – via maternal feed exposure during gestation and lactation – through young adulthood affected the production of antibodies. More specifically, they saw a decrease in the response of antibody-forming cells to an antigen (sheep red blood cells) at the highest concentration of TCPP tested, relative to the control group.
The results are consistent with past studies suggesting that maternal and developmental exposure to OPFRs, including TCPP, may affect life-long health and disease. This study supports further investigation of the immunologic effects of OPFRs. (JW)
Citation: Johnson VJ, Ryan K, Luster MI, Pandiri A, Hobbie K, Cora M, Shockley KR, Burleson GR, Xie G, Germolec DR. 2025. Developmental immunotoxicity study of tris(chloropropyl) phosphate (TCPP) in Hsd:Sprague Dawley® SD® rats exposed through dosed feed. Toxicol Sci kfaf006.
Active histone modifications occur independently of transcription
NIEHS researchers have shown that gene activity and histone modifications are connected in a more complicated way than originally thought.
In transcribing the genetic information stored in DNA into RNA, an enzyme known as RNA polymerase II (RNAP2) moves through chromatin, which is a complex of DNA tightly wrapped around proteins called histones. Various chemical changes or modifications to histones function to remodel chromatin to either permit or prohibit gene activity. However, the precise functional relationship between transcription and these active chromatin modifications is unclear.
To better define this relationship, the researchers used a substance called triptolide to trigger the breakdown of RNAP2 and inhibit the initiation of transcription. They then examined the impact on histone modifications. The researchers found that transcription initiation was not required for either hormone-induced or steady-state active histone modifications at transcription start sites and enhancers. Rather, blocking transcription initiation increased the levels of a specific type of modification called histone acetylation at active transcription start sites. Acetylation of histones alters accessibility to chromatin and allows DNA-binding proteins to interact with exposed sites to activate gene transcription and downstream cellular functions.
Together, the results demonstrate that active histone modifications occur independently of transcription. In addition, the findings suggest that the process of transcription coordinates the removal of these modifications to limit gene activity. (JW)
Citation: Hoffman JA, Trotter KW, Archer TK. 2025. RNA polymerase II coordinates histone deacetylation at active promoters. Sci Adv 11(6):eadt3037.
Phthalates, replacement chemicals may increase inflammation, oxidative stress in pregnancy
Exposure to mixtures of chemicals from consumer products during pregnancy is linked with increases in inflammation and oxidative stress, according to NIEHS researchers and their collaborators.
Phthalates and phenols are chemicals commonly present in many everyday products like packaging, disinfectants, and cosmetics. Prenatal exposure to these synthetic chemicals has raised concerns because they are linked to adverse pregnancy outcomes, such as abnormal fetal growth and preterm birth. While some of these chemicals are being replaced with alternatives, the effects of exposure to replacement chemicals during pregnancy remains poorly understood.
In this study, the researchers looked for associations between exposure to consumer product chemicals and a specific class of lipids known as oxylipins, which are involved in several key physiological functions. They used lipidomics, a technique that identifies lipids and their involvement in biosynthetic pathways, along with statistical approaches. Their analysis involved 901 participants from the LIFECODES Fetal Growth Study (2008-2018), an enriched case-cohort study of babies born at different ends of the growth spectrum. The researchers measured oxylipins in both urine and plasma to differentiate between inflammation and oxidative stress. They found a strong and consistent association between oxylipins produced across several biosynthetic pathways and increasing levels of phthalates and their replacement chemicals in pregnant women.
Altogether, the results provide new evidence indicating that exposure to consumer product chemicals, such as phthalates and their replacements, may disrupt specific biosynthetic pathways and adversely affect pregnancy outcomes. (SS)
Citation: Welch BM, Bommarito PA, Cantonwine DE, Milne GL, Stevens DR, Edin ML, Zeldin DC, Meeker JD, McElrath TF, Ferguson KK. 2025. Consumer Product Chemical Mixtures and Oxylipin-Mediated Inflammation and Oxidative Stress during Early Pregnancy: Findings from a Large US Pregnancy Cohort. Environ Sci Technol 59(6):2987-2999.
Nickel and trichloroethylene air emissions may affect breast cancer risk
Breast cancer incidence may be linked with air emissions of certain industrial chemicals, specifically nickel and trichloroethylene, according to a new study by NIEHS researchers and their collaborators.
Industrial facilities across the United States release hundreds of millions of pounds of toxic chemicals into the air yearly. Many industrial chemicals have known endocrine-disrupting or cancer-causing properties, making them relevant to breast cancer risk. However, evidence regarding specific industrial pollutants and breast cancer remains inconsistent, and the impact of pollutant mixtures has not been evaluated.
To address this gap, the researchers investigated whether air releases of 28 industrial chemicals was associated with incident breast cancer among a large, U.S.-wide group of women participating in the Sister Study. They quantified air emissions near residences of 46,150 women over a 10-year period. During study follow-up, researchers identified 4,155 breast cancer cases.
While most pollutants were not associated with breast cancer, the research team observed that women with higher levels of trichloroethylene or nickel compounds in the air near their homes each had 1.3 times greater risk of breast cancer compared to those who did not experience emissions of these compounds. The overall pattern of emission mixtures did not show a strong link to breast cancer incidence, although relatively rare patterns of high exposure to several compounds seemed to be associated with higher risk. According to the authors, further research to understand potential links between breast cancer and exposure to industrial pollutants, particularly in populations with a greater burden of exposure, are needed. (MD)
Citation: Ish JL, Madrigal JM, Pearce JL, Keil AP, Fisher JA, Jones RR, Sandler DP, White AJ. 2025. Industrial air emissions and breast cancer incidence in a United States-wide prospective cohort. Epidemiology; doi: 10.1097/EDE.0000000000001837 [Online 24 Jan. 2025 ahead of print].
Stressful life events precede the onset of autoimmune disorders
Negative life occurrences and psychological stress may contribute to the development of systemic autoimmune rheumatic diseases (SARDs), according to NIEHS researchers and their collaborators.
SARDs are multi-organ immune-mediated disorders thought to arise from the interaction of specific environmental exposures in genetically predisposed individuals. Growing evidence supports the role of psychosocial stress in the initial development of SARDs. However, the relationship between life events –– defined as social experiences that have a psychological impact on the individual, such as a divorce or a job promotion –– and SARDs is not well understood.
The researchers explored whether psychosocial stress may be linked to SARDs by investigating life events within the year prior to diagnosis in adult siblings, specifically in cases when one sibling was diagnosed with one of four SARDs and the other was not. They compared the siblings’ results to unrelated healthy participants enrolled in the study. Among the 227 participants who completed the questionnaire, those diagnosed with SARDs reported a higher frequency of life events compared to the unrelated control participants.
These events included negative life occurrences, such as uncontrollable, undesirable, and highly stressful events. Additionally, an increased odds of a SARD diagnosis was associated with higher perceived levels of stress corresponding to these events. According to the authors, these results call for prospective mechanistic studies to better understand the role of stress in the development of SARDs. (JW)
Citation: Bauer Ventura I, Goldberg ME, Schiffenbauer A, Shi M, Volochayev R, Jackson SH, Jansen A, Bayat N, Noroozi Farhadi P, Parks CG, Weinberg CR, Picardi A, Miller FW, Rider LG. 2025. Stressful life events are associated with the diagnosis of systemic autoimmune rheumatic diseases among adults. Clin Exp Rheumatol 43(1):21-27.
(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. Meklit Daniel is a fellow in the Environment and Cancer Epidemiology Group.)
