U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.


The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Environmental Factor

Environmental Factor

Your Online Source for NIEHS News

June 2024

Papers of the Month

How tobacco smoke may contribute to cervical cancer

Cigarette smoke condensate can activate cancer-related signaling pathways in human cervical cells immortalized with human papillomavirus (HPV), according to Division of Translational Toxicology researchers and their collaborators.

Cervical cancer is one of the most common causes of cancer deaths for American women. A major cause of cervical cancer is long-lasting infection with HPV. In some women, this infection may lead to precancerous lesions known as cervical dysplasia or cervical intraepithelial neoplasia. Tobacco smoke contributes to a greater cancer incidence and worse prognosis of cervical cancer. Carcinogens present in tobacco have been reported in the cervical mucus of women smokers; however, the underlying molecular mechanisms between cigarette smoking and cervical cancer remain unclear.

To address this knowledge gap, the researchers examined the potential effects of cigarette smoke condensate on human cervical epithelial cells immortalized with HPV. The findings provide evidence that exposure to cigarette smoke condensate can lead to cell proliferation, enhanced cell motility, and activation of receptor tyrosine kinases and transforming growth factor-beta signaling pathways. These pathways are important for the epithelial to mesenchymal transition (EMT), which is a biological process critical in cancer initiating events, such as cancer stem cell formation and in early and late stages of cancer cell metastasis.

According to the authors, understanding the molecular pathways and environmental factors that initiate EMT in ectocervical cells will help delineate molecular targets for intervention and define the role of EMT in the initiation and progression of cervical intraepithelial neoplasia and cervical cancer. (JW)

Citation: Mark ZA, Yu L, Castro L, Gao X, Rodriguez NR, Sutton D, Scappini E, Tucker CJ, Wine R, Yan Y, Motley E, Dixon D. 2024. Tobacco smoke condensate induces morphologic changes in human papillomavirus-positive cervical epithelial cells consistent with epithelial to mesenchymal transition (EMT) with activation of receptor tyrosine kinases and regulation of TGFB. Int J Mol Sci 25(9):4902.

Family history a risk factor for fibroid development

In a recent ultrasound study of Black and African American women conducted by NIEHS researchers, maternal history of uterine fibroids was associated with risk of fibroids and fibroid growth in daughters.

Uterine fibroids are benign tumors of the uterine muscle that develop in more than 70% of women of reproductive age. Symptomatic fibroids can result in substantial morbidity and are the leading indication for hysterectomy in the U.S. African American women experience fibroid onset an estimated 10 years earlier than White women and have a disproportionate health burden from fibroids. Previous studies of the importance of family history on fibroid development are limited by reliance on hospital-based participant selection, poorly defined measures of family history, and nonsystematic fibroid assessment..

To overcome these limitations, the researchers examined whether family history is a risk factor for fibroid development using prospective ultrasonography data. The prospective community cohort consisted of 1,610 Black and African American women from the Detroit, Michigan, area. The study was conducted from 2010-2018, using four standardized ultrasonographic examinations..

The results suggest that maternal history of fibroids was a risk factor for incident fibroids, especially when mothers were diagnosed at a younger age. Maternal history was also associated with increased fibroid growth. According to the authors, asking patients about their family history of fibroids could encourage patient self-advocacy and inform care. (JW)

Citation: Langton CR, Harmon QE, Baird DD. 2024. Family history and uterine fibroid development in Black and African American women. JAMA Netw Open 1;7(4):e244185.

Engineering key enzyme may improve heparin-based therapeutics

Engineering the properties of Heparosan synthase 2 from Pasteurella multocida (PmHS2) could be a promising strategy to improve the cost-effectiveness of heparin-based therapeutics, according to NIEHS researchers and their collaborators.

Heparan sulfates (HSs) are sulfated linear polysaccharides — large carbohydrate molecules containing many small sugar molecules joined chemically — that are widely distributed on the surface of mammalian cells and play important roles in physiological and disease states, including inflammation, cancer, and coagulation. Heparin, a heterogenous form of HS purified from pig mucosa, is commonly used as an anticoagulant to treat blood clots. Chemoenzymatic synthesis uses enzymes and chemistry to produce pure forms of HS, reducing the risk of contamination and potential side effects. Although PmHS2 is a key enzyme used in this process, the mechanism by which it generates these larger sugar molecules remains elusive.

To address this gap, the researchers reported the crystal structures of PmHS2 constructs with bound uridine diphosphate (UDP) and a cryo-electron microscopy (cryo-EM) structure of PmHS2 in complex with UDP and a heptasaccharide (NS 7-mer) substrate. By solving these structures and through various biochemical approaches, the researchers discovered that a shortened construct of PmHS2 (98-644) behaves as an active monomer rather than a dimer in solution. This mutant can perform the glyco-transfer reaction in the presence of higher substrate concentration with a larger catalytic efficiency.

Together, the results provide new evidence into the catalytic mechanism of PmHS2 and its involvement in heparosan oligomerization. According to the authors, engineering of PmHS2 could not only improve the cost-effectiveness of synthesis but might also increase the flexibility of the technique by allowing for the incorporation of novel modified saccharides into the oligosaccharide chain to treat a variety of diseases. (SS)

Citation: Stancanelli E, Krahn JA, Viverette E, Dutcher R, Pagadala V, Borgnia MJ, Liu J, Pedersen LC. 2024. Structural and functional analysis of heparosan synthase 2 from Pasteurella multocida to improve the synthesis of heparin. ACS Catal 14(9):6577-88.

Mutations related to stress response may induce antibiotic resistance

Mutations in genes related to a bacterial stress response may explain why certain pathogenic bacteria do not respond to antibiotic treatment, according to NIEHS researchers and their collaborators.

Pseudomonas aeruginosa is a Gram-negative bacterium that is a major cause of nosocomial infections, including burn infections, urinary tract infection, and pneumonia. It is also the leading cause of chronic lung infections in cystic fibrosis and chronic obstructive pulmonary disease patients. Antibiotic treatment remains challenging because P. aeruginosa is resistant to high concentrations of antibiotics and has a remarkable ability to acquire mutations conferring resistance to antimicrobial agents.

The researchers discovered a previously overlooked mechanism by which P. aeruginosa may acquire resistance to ciprofloxacin (cipro), an antibiotic commonly prescribed for the treatment of chronic P. aeruginosa infections. The results indicate that most P. aeruginosa cipro-resistant mutants in non-dividing or slow-dividing bacterial cultures owe their resistance to mutations that activate genes related to the Stringent Response. The Stringent Response is a stress response triggered by amino acid starvation, fatty acid limitation, iron limitation, heat shock, and other challenging conditions.

These results imply that mutations affecting the Stringent Response may be an important source of antibiotic resistance in P. aeruginosa. According to the authors, these mutations may play a crucial role at the early stages of an infection. One of the possible mechanisms by which activation of the Stringent Response may confer cipro tolerance is a series of genetic and epigenetic events alleviating oxidative stress, induced by this antibiotic. These findings may offer clinically relevant clues on preventing acquisition of antibiotic resistance. (JW)

Citation: García-Villada L, Degtyareva NP, Brooks AM, Goldberg JB, Doetsch PW. 2024. A role for the stringent response in ciprofloxacin resistance in Pseudomonas aeruginosa. Sci Rep 14:8598

How proteasome inhibitors may affect breast cancer biology

A new study reveals the mechanisms by which the 26S proteasome complex modulates the expression of gene networks intrinsic to breast cancer biology, according to NIEHS researchers.

The 26S proteasome is the major protein degradation machinery in cells. Cancer cells use the proteasome to modulate gene expression networks that promote tumor growth. Proteasome inhibitors have emerged as effective cancer therapeutics, but how they work mechanistically remains unclear.

The researchers demonstrated that breast cancer cells treated with the proteasome inhibitor MG132 exhibit profound changes in chromatin accessibility, the epigenome, and transcriptome dynamics. They uncovered unexpected reprogramming of the chromatin landscape and RNA polymerase II (RNAPII) transcription initiation.

The results showed that proteasome activity is required for both accessibility and transcription via specific cis-regulatory elements in the MCF-7 breast cancer cell genome. These cis-regulatory elements were representative of oncogenic super enhancer regions typically accessible in hormone receptor positive breast cancers, emphasizing the proteasome's role in regulating chromatin state and RNAPII transcription from genomic regions critical for breast tumor maintenance.

According to the authors, the study reveals an as yet uncharacterized molecular mechanism by which disruption of proteasome function affects the chromatin landscape, transcription, and expression of gene regulatory networks important in breast cancer biology. This research highlights the potential mechanism(s) underlying the anti-cancer effects of proteasome inhibitor drugs. (JW)

Citation: Kinyamu HK, Bennett BD, Ward JM, Archer TK. 2024. Proteasome inhibition reprograms chromatin landscape in breast cancer. Cancer Res Commun 16;4(4):1082-99.

(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.)

Back To Top