Rodent liver tumor study shows shared mutational patterns with human cancers

Rodent and human liver tumors share a similar mutational landscape, according to researchers from the Division of Translational Toxicology and Division of Intramural Research. The findings support the use of rodent models to study how environmental exposures contribute to liver cancer in people.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and the fourth leading cause of cancer-related deaths worldwide. Although environmental exposure to certain toxic chemicals is known to increase liver cancer risk, the specific ways they contribute to tumor formation and growth in humans remain unclear.

Toward this goal, the researchers sequenced exomes — the protein-coding regions of the genome — from HCCs in mice. Some of the tumors developed spontaneously due to aging, whereas others arose after long-term exposure to one of 10 potential human carcinogens. The study found that many of the carcinogens amplified the endogenous mutational processes, which led to higher incidences of tumor formation compared with their respective controls. Of note, exposure to higher doses of some drinking water disinfection byproducts resulted in an increase in the number of mutations and distinct mutational signatures in HCCs. Several of the mutational signatures observed in mice are also present in human cancers.

The authors believe the findings may have important public health implications regarding cancer risk assessment in humans. Future genomic studies in chemical carcinogenesis rodent models, as well as in human cohorts from suspected carcinogenic exposures, could provide further insight into the link between mutational signatures and other environmental carcinogens. (JW)

Citation: Xu M, Li J, Hsiao YC, Kovi RC, Li JL, Klimczak LJ, Riva L, Adams D, Bushel PR, Merrick BA, Gordenin D, Bucher JR, Sills RC, Pandiri AR. 2025. Environmental carcinogens often exacerbate endogenous mutagenic processes to enhance tumor promotion. Cell Rep 44(7):115978.

Pioneer transcription factors use stepwise process to remodel chromatin

A new study led by NIEHS researchers reveals how pioneer transcription factors (PTFs) work with other proteins to open compacted DNA regions — a key step in turning genes on or off.

PTFs are a special class of proteins that can bind to tightly packed chromatin — the complex of DNA and proteins that form chromosomes — and begin to loosen it. By making chromatin more accessible, PTFs pave the way for other transcription factors and protein complexes to regulate gene activity. They are essential for developmental processes and cellular reprogramming. However, it is not clear how PTFs recruit other partners and remodel chromatin structure.

To answer this question, the researchers studied a well-known PTF called GATA3 in breast cancer cells. They found that GATA3’s ability to open chromatin is enhanced by partnering with a transcription factor called AP-1. In addition, a protein complex called SWI/SNF, which uses energy from ATP to move or remove structural units of chromatin, appears to play a crucial role in changing chromatin architecture and enhancing GATA3 binding.

Together, the findings support a stepwise model of chromatin opening. First, GATA3 binding exposes the nucleosome, the basic structural unit of chromatin. Second, AP-1 helps to stabilize the exposed nucleosome. Third, SWI/SNF evicts the nucleosome. And finally, proteins that modify histones — the spool-like proteins around which DNA is wrapped — are then recruited to help activate transcription.

According to the authors, the results support what scientists call the dynamic-assisted loading model, which proposes that pioneering is a cooperative and energy-dependent process involving multiple transcription factors and chromatin remodelers. (JW)

Citation: Orlando KA, Grimm SA, Wade PA. 2025. Pioneering new enhancers by GATA3: role of facilitating transcription factors and chromatin remodeling. Nucleic Acids Res 53(11):gkaf473.

Smoking during pregnancy may affect DNA methylation of newborns

Babies born to mothers who continue smoking throughout pregnancy may experience changes in their DNA methylation patterns, according to NIEHS researchers and collaborators.

Tobacco smoke exposure before and during pregnancy is a common risk factor for health problems in newborns, such as lower infant birth weight and early respiratory illness. Some of these adverse health outcomes may be caused by changes in a biological process known as DNA methylation. DNA methylation involves the addition of chemical tags known as methyl groups to DNA, which affects the regulation and expression of genes. Previous studies have shown that continued maternal smoking can alter DNA methylation patterns in a newborn’s blood. However, the effects of other types of tobacco smoke exposure — such as paternal smoking before conception or secondhand smoke during pregnancy — on DNA methylation are not well understood.

The researchers examined the link between prenatal tobacco smoking exposures and DNA methylation patterns in blood from newborns through the Pregnancy and Childhood Epigenetics Consortium (PACE). Their analysis involved 11,175 parent-newborn pairs across 19 cohorts who contributed information on at least one prenatal smoking exposure, mainly through questionnaires. In a subset, maternal blood or urine was collected and tested for cotinine — a byproduct of nicotine — to verify exposure.

The researchers found a strong and consistent association between mothers who continued smoking throughout their pregnancy and changes in DNA methylation in their newborns’ blood. In contrast, they observed minimal DNA methylation changes linked to less-studied exposures, such as secondhand smoke, maternal smoking before pregnancy, and paternal smoking.

Altogether, the research points to potential biological mechanisms underlying smoking-related health risks in newborns. (SS)

Citation: Hoang TT, Cosin-Tomas M, Lee Y, Monasso G, Xu Z, Li SS, Zeng X, Starling AP, Reimann B, Röder S, Zillich L, Jima DD, Thio CHL, Pesce G, Kersten ETG, Breeze CE, Burkholder AB, Lee M, Ward JM, Consortium B, Alfano R, Deuschle M, Duijts L, Ghassabian A, Herrera LG, Jaddoe VW, Motsinger-Reif AA, Lie RT, Nawrot TS, Page CM, Send TS, Sharp G, Stein DJ, Streit F, Sunyer J, Wilcox AJ, Zar HJ, Koppelman GH, Annesi-Maesano I, Corpeleijn E, Snieder H, Hoyo C, Hüls A, Sirignano L, Witt SH, Herberth G, Plusquin M, Dabelea D, Yeung E, Wiemels JL, Richmond RC, Taylor JA, Felix JF, Håberg SE, Bustamante M, London SJ. 2025. Prenatal smoking exposures and epigenome-wide methylation in newborn blood. Environ Health Perspect; doi: 10.1289/EHP16303. [Online ahead of print 6 Jun 2025].

Emerging PFAS mixtures may pose broader metabolic risks

Newer per- and polyfluoroalkyl substances (PFAS), which are often used as replacements for phased-out PFAS compounds, may affect a broader range of metabolic pathways in the human body, according to NIEHS researchers and their collaborators. The results come from one of the first studies to examine how PFAS mixtures, particularly emerging PFAS, change over time and influence health.

PFAS have been broadly used in manufacturing and consumer products for decades and are known to disrupt metabolism and the endocrine system. Due to their resistance to degradation, they are ubiquitous in the environment and the human body. Although older PFAS have been studied extensively, relatively little is known about newer replacement chemicals, especially when they occur as mixtures and build up over time.

In this study, the researchers characterized both legacy and novel PFAS in 400 blood samples collected from 200 women during two time periods — 2007-2008 and 2013-2014. Legacy PFAS showed relatively consistent levels over time but declined overall. In contrast, novel PFAS increased in concentration and showed more variability across individuals and time points.

Of particular concern, mixtures of these newer PFAS were associated with disruptions in a wider spectrum of metabolic pathways compared with legacy PFAS mixtures. These pathways play key roles in energy balance, fat storage, and blood sugar regulation — all of which are relevant to chronic diseases such as cancer, diabetes, and cardiovascular conditions.

Taken together, the findings suggest that more research is warranted to investigate the health effects of novel PFAS compounds. (JW)

Citation: Chang CJ, Young AS, Keil A, Mullins CE, Liang D, Zhao S, Jones DP, Hu X, Walker DI, White AJ. 2025. Novel and legacy per- and polyfluoroalkyl substances in humans: long-term temporal variability and metabolic perturbations. Environ Int 201:109590.