Predicting the seizure risk posed by drugs

A new study from the NIEHS Division of Translational Toxicology revealed significant gaps in our understanding of chemicals that may trigger seizures in people.

Many experimental drugs fail in clinical trials because animal models do not reliably predict side effects such as seizures. Approximately one in 10 adults in the U.S. experience a seizure at some point in their lives. There is a strong need for methods to accurately predict seizure risk early in drug development.

To meet this need, the researchers used the adverse outcome pathway (AOP) framework, which documents molecular mechanisms underlying seizures by linking a trigger or key event to an adverse outcome. By combining this approach with computational tools and a wide range of published data, they identified 27 families of seizure-related targets, including neurotransmitter receptors, transporters, and certain calcium channels. Although 80% of the 196 seizure-inducing compounds identified had been tested in the lab, many families of targets were not represented in existing data sets.

According to the authors, the study calls for new efficient screening tests to cover the full range of seizure-relevant targets. Such tools could improve drug development, strengthen environmental risk assessments, and ultimately enhance regulatory decision-making to protect public health. (JW)

Citation: Behl M, Karmaus A, Rao M, Lane T, Harris J, Sachs C, Borrel A, Oyetade O, Unnikrishnan A, Hamm J, Hogberg HT. 2025. De-risking seizure liability: Integrating adverse outcome pathways (AOPs), new approach methodologies (NAMs) and in silico approaches while highlighting knowledge gaps. Toxicol Sci kfaf109.

Hormone therapy may alter breast cancer risk in women under 55

Hormone therapy may influence breast cancer risk for women under 55 years old, according to NIEHS researchers and collaborators.

Hormone therapy is commonly prescribed to ease symptoms of natural or surgical menopause. The relationship between hormone therapy and breast cancer risk has been studied extensively but almost entirely in postmenopausal women, leaving potential risks for premenopausal or perimenopausal women less understood.

The researchers conducted a large-scale analysis with data from about 460,000 women under 55 years old across North America, Europe, Asia, and Australia. They found that women treated with estrogen hormone therapy (E-HT) alone had a 14% lower incidence of breast cancer compared with those who never used hormone therapy. This protective effect was more evident among women who began E-HT at younger ages or used it for a longer time. However, women treated with estrogen plus progestin hormone therapy (EP-HT) had a 10% higher incidence of breast cancer compared with non-users. Moreover, this association was stronger among women who had not had gynecological surgery, where E-HT use is contraindicated.

These findings suggest that E-HT may reduce risk for young-onset breast cancer, whereas EP-HT may increase that risk. The study is consistent with prior studies of postmenopausal women and offers new evidence to guide clinical recommendations for hormone therapy in younger women. See related story. (MD)

Citation: O’Brien KM, House MG, Goldberg M, Jones ME, Weinberg CR, Berrington de Gonzalez, et al. 2025. Hormone therapy use and young-onset breast cancer: A pooled analysis of prospective cohorts included in the Premenopausal Breast Cancer Collaborative Group. Lancet Oncol 26(7):911-23.

Transient errors in DNA replication may drive mutations

A new study led by NIEHS researchers reveals how mutations form in nuclear DNA, a key step in understanding both evolution and disease development.

DNA replication — the process of copying genetic material — is usually very accurate. However, mistakes such as mismatches can occur when DNA polymerases, the enzymes that copy new DNA strands, insert the wrong building block, or nucleotide. To investigate how such errors arise, the team studied three DNA polymerases (called Pol alpha, Pol delta, and Pol epsilon) in the model organism Saccharomyces cerevisiae (budding yeast).

The researchers tested eight possible mutation pathways, including four well-known routes and four newer ones called transient initiator mutagenesis (TIM) pathways.

They performed mutation accumulation experiments and whole genome sequencing to track how single-base errors are generated in five yeast strains containing mutations in the polymerase and proofreading sites of the DNA Polymerases alpha, delta, and epsilon. They discovered that certain single-base mutations seemed to cluster near the ends of the new DNA strands. The results suggest that the four TIM pathways were the source of these replication errors.

Together, these findings point toward a potential biological mechanism for how DNA replication errors drive genetic variation. This work enhances understanding of how mutations shape evolution and contribute to diseases such as cancer. (SS)

Citation: Lujan SA, Zhou ZX, Kunkel TA. 2025. Evidence that transient replication errors initiate nuclear genome mutations. Nucleic Acids Res 53(14):gkaf679.

Rixosome revealed to contain a stable core, flexible enzymatic modules

NIEHS researchers and their collaborators have mapped the architecture of the rixosome — a large “Swiss army knife-like” protein complex packed with molecular tools that regulate cellular functions.

The rixosome participates in RNA decay during processes such as assembly of the ribosome, a cellular structure that serves as the site of protein synthesis. It also plays an important role in maintaining heterochromatin, a tightly packed form of DNA characterized by its condensed structure. Yet the overall architecture of the rixosome has been hard to visualize because parts of it — called intrinsically disordered regions (IDRs) — lack a fixed 3D structure.

Using structural and biochemical techniques, the researchers showed that a protein called PELP1 serves as the central scaffold of the rixosome. Enzymatic subunits assemble on a specific part of PELP1, an IDR that is rich in two types of amino acids called proline and glutamic acid. This flexible section helps PELP1 connect with another protein called SENP3. This protein is a SUMO-specific protease, which means it removes small proteins called SUMOs (small ubiquitin-like modifiers) that act like tags to control how a protein behaves, thereby regulating several key protein functions and gene activity.

Although SENP3 is associated with human diseases such as cancer, heart disease, and neurological disorders, it has not been clear how its protease activity is controlled. According to the authors, this research uncovers an activation mechanism for the SENP3 protease that could lay the groundwork for structural-based design of SENP3-specific protease inhibitors/regulators to treat cancer. (JW)

Citation: Gordon J, Kaminski AM, Bommu SR, Skrajna A, Petrovich RM, Pedersen LC, McGinty RK, Warren AJ, Stanley RE. 2025. PELP1 coordinates the modular assembly and enzymatic activity of the rixosome complex. Sci Adv 11(30):eadw4603.