Papers of the Month
Intramural
By Janelle Weaver, Sam Tyler, and Shruti Somai
Some flame retardants may still pose a health concern
Organophosphorus flame retardants (OPFRs) may not effectively replace certain phased-out brominated flame retardants (BFRs), and in some instances, they might exhibit higher potency, according to researchers from the Division of Translational Toxicology.
OPFRs are abundant and persistent in the environment but have limited toxicity information. Their similarity in structure to organophosphate pesticides presents great concern for developmental neurotoxicity (DNT). However, current in vivo testing is not suitable to provide DNT information on the amount of OPFRs that lack data.
In this new study, the researchers performed an integrated approach analyzing data from a battery of in vitro assays and behavioral data of small model organisms, data from the integrated chemical environment (ICE), in vitro and in vivo literature data, as well as human biomonitoring and exposure data. They also applied physiologically-based toxicokinetic models to relate in vitro toxicity data to human exposure based on maximum plasma concentration. In addition, the researchers evaluated eight OPFRs and selected two representative BFRs with known DNT potential for toxicity benchmarking.
Data from the DNT battery indicated that the aromatic OPFRs have activity at similar concentrations as the BFRs and should therefore be evaluated further. Overall, this case study indicates that human exposure to some OPFRs could lead to a plasma concentration similar to those exerting in vitro activities, indicating potential concern for human health. According to the authors, the study addresses concerns regarding the impact of environmental chemicals on the increase in neurodevelopmental disorders and advocates for more stringent regulations. (JW)
Citation: Kreutz A, Oyetade OB, Chang X, Hsieh JH, Behl M, Allen DG, Kleinstreuer NC, Hogberg HT. 2024. Integrated approach for testing and assessment for developmental neurotoxicity (DNT) to prioritize aromatic organophosphorus flame retardants. Toxics 12(6):437.
Exploring an anti-cancer target
A protein called Polγ could hold potential for the treatment of pancreatic cancer, according to NIEHS researchers and their collaborators.
The replicative mitochondrial DNA polymerase, Polγ, and its protein regulation are essential for the integrity of the mitochondrial genome. The intricacies of Polγ regulation and its interactions with regulatory proteins, which are essential for fine-tuning polymerase function, remain poorly understood. Misregulation of the Polγ heterotrimer, consisting of PolG, the polymerase catalytic subunit, and PolG2, the accessory subunit, ultimately results in mitochondrial diseases.
The researchers used single particle cryo-electron microscopy to resolve the structure of Polγ. Chemical crosslinking mass spectrometry and site-directed mutagenesis uncovered the region where a protein called LonP1 engages with PolG, promoting proteolysis and regulation of PolG protein levels. PolG2 clinical variants, which disrupted a stable Polγ complex, led to enhanced LonP1-mediated PolG degradation. Overall, this insight into Polγ aids in an understanding of mitochondrial DNA replication and characterizes how machinery of the replication fork may be targeted for proteolytic degradation when improperly functioning.
According to the authors, the spectrum of the downstream implications of LonP1 targeting PolG is currently unknown. However, future work could explore targeting the interaction sites of PolG and PolG2 as a potential therapeutic in pancreatic cancer. (JW)
Citation: Riccio AA, Brannon AJ, Krahn JM, Bouvette J, Williams JG, Borgnia MJ, Copeland WC. 2024. Coordinated DNA polymerization by Polγ and the region of LonP1 regulated proteolysis. Nucleic Acids Res 52(13):7863-75.
Residential sources of toxic metals may vary by population
Living in closer proximity to chromium- and lead-releasing facilities may be related to higher levels of metals in Black women, particularly those residing in the most disadvantaged areas, according to NIEHS researchers and their collaborators.
Exposure to toxic metals has been linked with adverse health outcomes, but it is unclear whether people who live near facilities that emit airborne metals have higher amounts of metals in their bodies.
To address this, researchers measured toenail concentrations of arsenic, cadmium, cobalt, chromium, and lead in a sample of 1,556 non-Hispanic Black (32.5%) and non-Hispanic White (67.5%) women from the Sister Study. In addition, they identified metal-emitting industrial facilities within 3, 5, and 10 kilometers of the participants’ baseline residences. The authors examined associations between industrial metal emissions from nearby facilities and toenail metal concentrations, with consideration of how the association varied by race and neighborhood deprivation.
The results revealed that non-Hispanic Black participants were more likely than non-Hispanic White participants to reside within 3 kilometers of chromium-releasing facilities, and within 5, and 10 kilometers of all observed metal-emitting sites. The authors observed that higher chromium emissions were related to higher chromium toenail levels for non-Hispanic Black women, but not non-Hispanic White women. In addition, living closer to lead sites was associated with higher toenail lead levels among Black women who were living in areas with higher deprivation. According to the authors, more research is needed to better characterize residential sources of toxic metals and to consider how these sources of exposure may vary in different populations. (ST)
Citation: Daniel M, Ish JL, Madrigal JM, Chang CJ, Lawrence KG, Fisher JA, Levine KE, Trottier BA, Jones RR, Sandler DP, White AJ. 2024. Residential proximity to toxic metal-emitting industrial sites and toenail metal concentrations in a United States-wide prospective cohort. Environ Res 258:119446.
Phenol exposure during infancy may increase risk of obesity
Exposure to environmental phenols during infancy may be linked with an increased risk of obesity, according to NIEHS researchers and their collaborators.
Phenols — highly prevalent endocrine-disrupting chemicals (EDCs) — are commonly used in a variety of consumer and industrial products. Exposure to environmental phenols can perturb hormonal functions and interfere with normal health and development. Although infants may be more susceptible to phenols, few studies have evaluated phenol exposures during this important developmental window.
To address this knowledge gap, the researchers examined the link between environmental phenol exposures and body mass index (BMI), which may be influenced by EDCs, in a U.S.-based cohort of 199 infants born between 2010 and 2014. The authors evaluated the levels of seven urinary phenols at ages 6-8 and 12 weeks and assessed corresponding BMI z-scores between birth and 36 weeks. The researchers found a strong and consistent association between environmental phenol exposure and a rapid increase in BMI z-score in these infants.
Together, the results provide new evidence indicating that phenol exposure during infancy may dysregulate infant growth, which could affect cardiometabolic health and obesity at a later stage. According to the authors, further research is warranted to evaluate dose-response relationships and to assess potential long-term health effects of phenol exposure during infancy. (SS)
Citation: Stevens DR, Goldberg M, Adgent M, Chin HB, Baird DD, Stallings VA, Sandler DP, Calafat AM, Ford EG, Zemel BS, Kelly A, Umbach DM, Rogan W, Ferguson KK. 2024. Environmental phenols and growth in infancy: the Infant Feeding and Early Development Study. J Clin Endocrinol Metab dgae307.
Mitigating herpes simplex virus type 1 infection
New findings reveal a beneficial role for α7 nicotinic acetylcholine receptors (α7 nAChRs) expressed on microglia during herpes simplex virus type 1 (HSV-1) infection, according to NIEHS researchers and their collaborators.
HSV-1 is a DNA virus that establishes latency in neural tissues, with reactivation causing severe consequences, such as encephalitis. Emerging evidence links HSV-1 infection to chronic neuroinflammation and neurodegenerative diseases. Microglia, the central nervous system’s immune sentinels, express diverse receptors, including α7 nAChRs, which are critical for immune regulation. Recent studies suggest α7 nAChR activation protects against viral infections.
The researchers show that α7 nAChR agonists, choline and PNU-282987, significantly inhibit HSV-1 replication in microglial cells. The findings suggest a novel mechanism by which microglial α7 nAChRs restrict viral infections by regulating innate immune responses. In addition, activation of α7 nAChRs enhances antiviral pro-inflammatory factors. This could inhibit HSV-1 replication in the cells and mitigate the risk of recurrent infections, potentially affecting long-term neurodegeneration.
According to the authors, further studies assessing the in vivo effects of traditional or silent α7 agonists on HSV-1 replication will be critical for determining if activation of α7 nAChRs on microglia can prevent severe HSV-1 central nervous system infection, avert low-grade chronic neuroinflammation, or reduce the risk of neurodegeneration. (JW)
Citation: Chen SH, Damborsky JC, Wilson BC, Fannin RD, Ward JM, Gerrish KE, He B, Martin NP, Yakel JL. 2024. α7 nicotinic receptor activation mitigates herpes simplex virus type 1 infection in microglia cells. Antiviral Res 228:105934.
(Janelle Weaver, Ph.D., is a contract writer for the NIEHS Office of Communications and Public Liaison and Sam Tyler is a technical writer-editor in the same office. Shruti Somai, Ph.D., is a visiting fellow in the Genome Integrity and Structural Biology Laboratory.)
