Papers of the Month
Intramural
By Janelle Weaver and Meklit Daniel
Standardizing zebrafish studies for toxicology testing
Zebrafish experiments across different laboratories produce generally consistent results regarding test substances’ activity, but not their potencies, according to researchers from the Division of Translational Toxicology.
Embryonic zebrafish represent a useful test system to screen substances based on their ability to perturb development. However, the exposure scenarios, endpoints captured, and data analyses vary among the laboratories that conduct screening. A lack of harmonization impedes the comparison of substance potency and toxicity outcomes across laboratories and may hinder the broader adoption of this model for regulatory use.
To address this problem, the researchers developed the Systematic Evaluation of the Application of Zebrafish in Toxicology (SEAZIT) initiative to investigate the sources of variability in toxicity testing. This initiative involved an interlaboratory study to determine whether experimental parameters altered the developmental toxicity of a set of 42 substances in three diverse laboratories.
The researchers observed reasonable agreement across the three laboratories as 33 of 42 test substances (78.6%) had the same activity call (i.e., a test substance generated a response [active] vs. no response [inactive]). However, the differences in potency seen using variable in-house protocols emphasize the importance of harmonizing exposure variables under evaluation. According to the authors, the lessons learned from the study emphasize the potential benefits of standardized testing protocols for the zebrafish research community interested in toxicology testing. (JW)
Citation: Hamm JT, Hsieh JH, Roberts GK, Collins B, Gorospe J, Sparrow B, Walker NJ, Truong L, Tanguay RL, Dyballa S, Miñana R, Schiavone V, Terriente J, Weiner A, Muriana A, Quevedo C, Ryan KR. 2024. Interlaboratory study on zebrafish in toxicology: Systematic Evaluation of the Application of Zebrafish in Toxicology's (SEAZIT's) evaluation of developmental toxicity. Toxics 12(1):93.
Personal care product use during puberty may affect breast cancer risk
Frequent use of personal care products (PCPs) during puberty may lead to increased breast cancer rates later in life, according to NIEHS researchers. The study is the first to investigate the use of “everyday” PCPs, such as makeup and skincare products, around the time of puberty in relation to breast cancer incidence.
Many PCPs contain endocrine-disrupting chemicals that may affect breast cancer risk. Racial and ethnic differences in PCP use patterns and the chemicals in products marketed to specific groups may contribute to breast cancer disparities. Breast tissue undergoes rapid changes during puberty and may be vulnerable to the effects of chemicals in PCPs.
To examine how use of 37 everyday PCPs during puberty may affect breast cancer incidence, the researchers analyzed self-reported data from 4,049 Black, 2,104 Hispanic, and 39,312 White women in the Sister Study. PCP use patterns at ages 10-13 years were not clearly linked with breast cancer diagnosis. However, breast cancer rates were elevated among Black women who reported frequent nail and perfume product use during puberty and among Black and Hispanic women who reported frequent hair product use during the same period.
According to the authors, these findings provide some evidence that frequent PCP use during puberty is associated with increased breast cancer risk, especially among racially and ethnically minoritized groups. More research is needed to determine whether reducing PCP use during this critical developmental window may reduce breast cancer risk.
Citation: Goldberg M, Chang CJ, Ogunsina K, O'Brien KM, Taylor KW, White AJ, Sandler DP. 2024. Personal care product use during puberty and incident breast cancer among Black, Hispanic/Latina, and White women in a prospective US-wide cohort. Environ Health Perspect 132(2):27001. (MD)
Autoantibodies signal poor prognosis for inflammatory condition
Myositis-associated autoantibodies (MAAs) are a prevalent marker of poor prognosis for patients with juvenile myositis, according to NIEHS researchers and their collaborators.
Myositis is a medical condition characterized by inflammation affecting the muscles. The manifestations of this condition may include skin issues, muscle weakness, and the potential involvement of other organs. MAAs are immune system proteins that are directed against one or more of the individual's own proteins. They are present in patients with myositis and other autoimmune connective tissue diseases. Overall, MAAs remain largely uncharacterized in juvenile-onset myositis. Moreover, it is unknown whether the number of MAAs is associated with disease severity.
To this end, the researchers characterized the prevalence, clinical features, and outcomes associated with MAAs in a large North American cohort of patients with juvenile-onset myositis. Among 551 patients, 36% had an MAA and 13% had more than one MAA.
MAA positivity was associated with certain clinical features, including Raynaud phenomenon and interstitial lung disease, as well as a chronic disease course and mortality. The number of MAAs also was associated with mortality. According to the authors, prospective studies are needed to determine whether early detection of MAAs may lead to improved outcomes for patients with juvenile myositis. (JW)
Citation: Sherman MA, Noroozi Farhadi P, Pak K, Trieu EP, Sarkar K, Targoff IN, Neely ML, Mammen AL, Rider LG; Childhood Myositis Heterogeneity Collaborative Study Group. 2024. Myositis-associated autoantibodies in juvenile myositis are associated with refractory disease and mortality. Arthritis Rheumatol; doi: 10.1002/art.42813. [Online ahead of print 25 Jan. 2024].
How smoking affects DNA methylation
Thousands of DNA methylation patterns have been linked to smoking, and most revert to normal within one year of quitting, according to NIEHS researchers and their collaborators.
Smoking causes adverse health outcomes throughout life as well as alterations in DNA methylation — a biological process by which methyl groups are added to the DNA molecule. Although it is well established that smoking leads to changes in DNA methylation at specific CpG sites, several important research gaps remain.
To address these knowledge gaps, the researchers analyzed data from 15,014 adults from four studies. They identified several thousand CpGs linked to smoking. The results also showed that the effects of smoking on DNA methylation can be largely reversed within one year of quitting. However, 25% of CpGs did not attenuate within one year. Smoking-related methylation at some CpG sites may differ by sex or dietary factors. In addition, exposure to smoking during pregnancy alters DNA methylation with effects that last into adulthood.
Taken together, the results address important gaps regarding impacts of smoking on methylation with potential insights into smoking-related health outcomes, many of which persist after quitting. Moreover, the findings demonstrate that pregnancy is a vulnerable window of susceptibility that can alter DNA methylation throughout life. (JW)
Citation: Hoang TT, Lee Y, McCartney DL, Kersten ETG, Page CM, Hulls PM, Lee M, Walker RM, Breeze CE, Bennett BD, Burkholder AB, Ward J, Brantsæter AL, Caspersen IH, Motsinger-Reif AA, Richards M, White JD, Zhao S, Richmond RC, Magnus MC; BIOS Consortium; Koppelman GH, Evans KL, Marioni RE, Håberg SE, London SJ. 2024. Comprehensive evaluation of smoking exposures and their interactions on DNA methylation. EBioMedicine 100:104956.
Outdoor air pollution may be linked to uterine cancer in U.S. women
Residential exposure to nitrogen dioxide (NO2), a possible proxy for vehicular traffic-related pollution, is associated with a higher incidence of uterine cancer among U.S. women, according to NIEHS researchers and their collaborators.
Outdoor air pollution consists of a heterogenous mixture of compounds, some of which may function as endocrine disruptors and therefore may be particularly relevant to hormone-related health conditions. For example, NO2 has been consistently associated with a higher risk of breast cancer. However, few studies have examined the relationship between ambient air pollution and uterine cancer.
To address this gap, the researchers investigated whether residential exposure to outdoor air pollution — specifically NO2 and fine particulate matter (PM2.5) — was associated with uterine cancer incidence among 33,417 women in the NIEHS Sister Study cohort. Although no association was observed for PM2.5, a five parts-per-billion increase in NO2 was associated with a 20% higher incidence of uterine cancer. This association for NO2 was also particularly apparent in women living in urban areas, but not those in rural or suburban areas.
These findings suggest a relationship between traffic-related emissions and uterine cancer, thus expanding the scope of health effects associated with outdoor air pollution and highlighting the need for policy and other interventions to reduce air pollutant levels.
Citation: Brown JA, Ish JL, Chang CJ, Bookwalter DB, O'Brien KM, Jones RR, Kaufman JD, Sandler DP, White AJ. 2024. Outdoor air pollution exposure and uterine cancer incidence in the Sister Study. J Natl Cancer Inst djae031. (MD)
(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.)
