Papers of the Month
By Victoria Placentra, Prashant Rai, Saniya Rattan, Payel Sil, and Nancy Urbano
Butylparaben exposure targets the liver in rats
Researchers from the Division of the National Toxicology Program studied the effects of butylparaben (BP) exposure on reproductive fitness and development in rats. BP is a member of the paraben family, a group of chemicals that has antimicrobial and antifungal properties. Parabens are used liberally in consumer products including food and cosmetics. Human exposure to parabens is widespread, but studies report conflicting evidence of the effects of exposure in rodents.
In this study, multiple generations of rats were orally exposed to varying concentrations of BP through different stages of life. This approach, known as a multigeneration continuous breeding study, allowed for more statistical power compared to other methods to analyze parameters of reproduction and development. These parameters included bodyweight, pregnancy rate, litter size, mortality, sperm quality, pubertal onset, and endocrine signaling.
The researchers found BP dose-related decreases in bodyweight across all three generations of rats. The liver was identified as the primary target organ of BP toxicity due in part to increased liver weights and nonneoplastic lesions. All other measurements regarding fertility and potential endocrine disruption were not related to BP exposure. (VP)
Citation: Hubbard TD, Brix A, Blystone CR, McIntyre BS, Shockley K, Cunny H, Waidyanatha S, Turner KJ, McBride S, Roberts GK. 2020. Butylparaben multigenerational reproductive assessment by continuous breeding in Hsd:Sprague Dawley SD rats following dietary exposure. Reprod Toxicol 96:258–272.
Novel study links microbiota in house dust with adult allergy
Microbial diversity found in house dust may influence allergic outcomes in adults, according to NIEHS scientists and their collaborators. The work is the first large-scale study to use a high throughput sequencing method to show that exposure to several different groups of bacteria in house dust was associated with asthma, hay fever, and atopy. The research provides novel insights into the indoor bacterial communities that could either protect or exacerbate allergic outcomes.
The study analyzed microbial communities in dust samples of bedrooms from 879 independent households that participated in the National Institutes of Health Agricultural Lung Health Study, a case-control asthma study. Bacterial communities were characterized by high-throughput sequencing of the 16S rRNA gene, which exists in the genome of all bacteria and is unique to each bacterial type. Specific bacteria, such as ones from Cyanobacteria and Bacteroidetes, were more abundant in the house dust of residents with asthma, atopy, or hay fever. Interestingly, another group of bacteria from Firmicutes were less abundant in homes of individuals without these allergies. The results of this study lend support to the hygiene hypothesis, which suggests that childhood exposure to diverse microbes could lead to lower prevalence of allergies. (PR)
Citation: Lee MK, Wyss AB, Carnes MU, Richards M, Parks CG, Beane Freeman LE, Thorne PS, Umbach DM, Azcarate-Peril MA, Peddada SD, London SJ. 2020. House dust microbiota in relation to adult asthma and atopy in a U.S. farming population. J Allergy Clin Immunol; doi:10.1016/j.jaci.2020.06.013 [Online 29 June 2020]. (Story)
Dioxin causes DNA methylation modifications
NIEHS researchers and their collaborators identified 116 unique locations of DNA methylation in blood DNA of participants exposed to dioxin-like environmental toxins. Methylation, when methyl groups attach to DNA, occurred in 116 areas where nucleotides cytosine and guanine are paired together, called CpG sites. The study is the first to use an Illumina 850K methylation array to examine how dioxin-like compounds affect DNA and provides a framework for understanding how these chemicals affect human health.
Using data collected from the Anniston Community Health Survey in Alabama, the authors examined the effects of exposure to dioxin-like compounds, such as polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyl (PCBs). The authors determined that most of the CpGs were associated with PCDD exposure, the most dioxin-like of the exposures they measured. PCDD exposure in African- Americans was markedly higher, and the effects were observed at CpG (cg21401636) in the Kinesin Family Member 5C (KIF5C) gene region. The CpGs were found in gene regulatory regions of the transcriptional factors FOXP2, FOXA1, and FOXA2 and may represent a group of CpGs in blood cell types that are particularly susceptible to dioxin exposure. While the effect of these modifications is not completely understood, the changes in DNA methylation patterns are apparent. (PS)
Citation: Pittman GS, Wang X, Campbell MR, Coulter SJ, Olson JR, Pavuk M, Birnbaum LS, Bell DA. 2020. Dioxin-like compound exposures and DNA methylation in the Anniston Community Health Survey Phase II. Sci Total Environ 742:140424.
Cholesterol 25-hydroxylase regulates inflammatory responses in the lung
Cholesterol 25-hydroxylase (CH25H), a lipid synthesis enzyme previously unstudied in lung biology, plays a central role in lung inflammation, according to NIEHS researchers and their collaborators. With the help of genetically modified mice that lack CH25H, scientists identified an inducible metabolic axis that programs lung immune cell activity. Specifically, this study identifies a role for CH25H in clearance of neutrophils from the lung following inflammation.
CH25H is expressed in macrophages throughout the body. However, the expression of CH25H in alveolar macrophages far exceeds that of macrophages in other tissues. Macrophages are tissue-resident white blood cells that detect and destroy invading microorganisms within the body and also play a critical role in inflammation. The researchers were able to expose genetically modified mice to lipopolysaccharide, a molecule normally found on the surface of bacteria, to create an inflammatory reaction in the lungs and to test the role of CH25H. They determined that CH25H and its product, the lipid 25-hydroxycholesterol (25HC), act in a metabolic axis to program alveolar macrophages to resolve neutrophilic inflammation in the lungs. These data may help identify a new inflammatory pathway specific to macrophages in the lung and further scientists’ understanding of how inflammation is initiated and resolved. (SR)
Citation: Madenspacher JH, Morrell ED, Gowdy KM, McDonald JG, Thompson BM, Muse G, Martinez J, Thomas S, Mikacenic C, Nick JA, Abraham E, Garantziotis S, Stapleton RD, Meacham JM, Thomassen MJ, Janssen WJ, Cook DN, Wurfel MM, Fessler MB. 2020. Cholesterol 25-hydroxylase promotes efferocytosis and resolution of lung inflammation. JCI Insight 5(11):e137189.
Super-enhancers drive estrogen responses
NIEHS scientists are the first to identify super-enhancer (SE) region interactions that underlie hormonal regulation of genes in uterine tissue. The work also sheds light on optimal development of estrogen responses in the uterus. By discovering how SEs are involved in estrogen regulation, researchers have a new target for helping people with uterine insensitivity problems.
Team members used high-throughput chromosome conformation capture and DNA sequence analysis on female mice and found that most SEs are located at the end of a chromatin loop. They also determined that most uterine genes associated with these SEs are regulated by estrogen. This work confirms previous work done in vitro. It highlights the association between uterine maturation and gene regulation and how the association with super-enhancers can have an influence on pubertal development. However, they are not as important to uterine development as other retinoic acid receptors and homeobox D. SE-associated genes produced the best estrogen receptor alpha (ERalpha) mediated expression after reproductive maturity, suggesting that pubertal processes that occur after SE assembly and ER-alpha binding are needed for governing gene responses. (NU)
Citation: Hewitt SC, Grimm SA, Wu SP, DeMayo FJ, Korach KS. 2020. Estrogen receptor alpha (ERalpha)-binding super-enhancers drive key mediators that control uterine estrogen responses in mice. J Biol Chem 295(25):8387–8400.
(Victoria Placentra is an Intramural Research Training Award [IRTA] postbaccalaureate fellow in the NIEHS Mutagenesis and DNA Repair Regulation Group. Prashant Rai, Ph.D., is a visiting fellow in the NIEHS Clinical Investigation of Host Defense Group. Saniya Rattan, Ph.D., is an IRTA fellow in the NIEHS Reproductive Developmental Biology Group. Payel Sil, Ph.D., is a contractor in the NIEHS Biostatistics and Computational Biology Branch. Nancy Urbano is an IRTA postbaccalaureate fellow in the NTP Predictive Toxicology and Screening Group.)