Papers of the Month
By Janelle Weaver
How proteins in cardiac muscle cells regulate recovery from heart damage
A protein called soluble epoxide hydrolase (sEH) is abundant in the heart, where it degrades a metabolite that improves recovery after reduced blood flow, according to NIEHS researchers and their collaborators.
sEH breaks down and diminishes the benefits of signaling molecules called epoxyeicosatrienoic acids (EETs), which have potent, wide-ranging biological effects. When blood flow to the heart is restricted, EETs can increase the delivery of oxygen and nutrients to heart muscle tissue, and EET-induced signaling protects cardiac muscle cells against damage. While EET treatment or sEH inhibition both protect against injury after reduced blood flow to the heart, numerous questions remain.
To address this knowledge gap, the researchers examined the specific roles of sEH in cardiac cell types in mice. The results showed that sEH is most abundant and active in heart muscle cells (cardiomyocytes), where it regulates the breakdown of EETs that improve cardiac function after blood flow restriction. In contrast, sEH in endothelial cells does not play a significant role in these processes. In addition, sEH was not detectable in cardiac smooth muscle cells or fibroblasts. Taken together, the findings revealed cell-specific physiological roles of sEH-mediated EET breakdown in the heart.
Citation: Edin ML, Gruzdev A, Bradbury JA, Graves JP, Lih FB, DeGraff LM, Fleming I, Zeldin DC. 2023. Disruption of Ephx2 in cardiomyocytes but not endothelial cells improves functional recovery after ischemia-reperfusion in isolated mouse hearts. J Biol Chem 299(4):103049.
Infant girls may vary in their minipubertal response
The timing and magnitude of the minipuberty response differ across healthy infant girls, according to NIEHS researchers and their collaborators.
During infancy, there is a transient activation of the hypothalamic pituitary gonadal axis — a critical signaling pathway for reproductive function. But the importance of this period, known as minipuberty, is not well understood, especially in girls.
To address this knowledge gap, the researchers focused their analysis on anti-Müllerian hormone (AMH), which is produced in ovarian follicles and may reflect an infant’s ovarian development. The researchers measured AMH in 153 healthy girls, from 1,366 blood samples collected across 11 visits during the first nine months of life, as part of the Infant Feeding and Early Development Study.
Previous research from smaller studies and less longitudinal data reported that AMH peaks at three to four months of age, followed by a decline at approximately one year. In the current study, researchers found that AMH trajectories differed among the infants and could be grouped into four distinct clusters that represent patterns of AMH: 1) AMH starts high and decreases; 2) AMH peaks at about 12 weeks; 3) AMH peaks at about 20 weeks; and 4) AMH is consistently low.
These groups differed in their follicle-stimulating hormone (FSH) trajectories, timing of estradiol production, and ovarian characteristics. Of note, clusters 2 and 3 reflect the AMH pattern previously reported, but the patterns seen in clusters 1 and 4 have not been described previously. Cluster 1 infants had the highest overall AMH concentrations, similar to results from a small study of infants whose mothers had polycystic ovarian syndrome. Cluster 4 infants, with their consistently low AMH, displayed a longer period of elevated FSH and a delayed estradiol response, suggesting potential involvement of hypothalamic-pituitary signaling. According to the authors, follow-up is needed to explore possible links between the AMH patterns and later gynecologic conditions.
Citation: Chin HB, Krall JR, Goldberg M, Stanczyk FZ, Darge K, Stallings VA, Rogan WJ, Umbach DM, Baird DD. 2023. Early life anti-Müllerian hormone trajectories in infant girls. Epidemiology; doi: 10.1097/EDE.0000000000001610. [Online 16 March 2023].
Digging deeper into diabetes and the neighborhood environment
Living in what is perceived as less socially cohesive neighborhoods in terms of trust and social support is generally linked to a higher prevalence of type 2 diabetes mellitus (T2DM), but this relationship varies across age, sex or gender, and race and ethnicity, according to NIEHS researchers and their collaborators.
Previous studies have shown that the prevalence of T2DM is lower in neighborhoods perceived as having high social cohesion, which reflects the degree of connectedness, solidarity, and trust among people within a community. Yet, few studies have investigated this relationship among a large, racially and ethnically diverse, and nationally representative sample of the U.S. population.
To address this knowledge gap, the researchers examined associations between perceived neighborhood social cohesion and T2DM overall and at the intersection of age, sex or gender, and race and ethnicity using National Health Interview Survey data (2013-2018) collected from 170,432 adults. Consistent with past research, low perceived neighborhood social cohesion was associated with a higher prevalence of T2DM overall.
In particular, a higher prevalence of T2DM in neighborhoods with low versus high perceived social cohesion was observed among participants 31-49 years old and among Hispanic or Latinx women between the ages of 18 and 30 years. By contrast, Non-Hispanic Black women aged 18 to 30 years had a lower prevalence of T2DM in neighborhoods with medium versus high perceived social cohesion. According to the authors, the study demonstrates the importance of considering how multiple social identities intersect and interact with the neighborhood environment to influence health.
Citation: Williams PC, Alhasan DM, Gaston SA, Henderson KL, Braxton Jackson W 2nd, Jackson CL. 2023. Perceived neighborhood social cohesion and type 2 diabetes mellitus by age, gender, and race/ethnicity in the United States. Prev Med 170:107477.
Crystal structures shed light on molecules driving allergies to pets
New research reveals the types of molecules that bind to two major allergens found on pets called Can f 1 and Fel d 7, according to NIEHS scientists and their collaborators.
Dogs and cats are important sources of indoor allergens that affect 10%-20% of the population. Pet lipocalins, such as Can f 1 and Fel d 7, are respiratory allergens that bind to molecules, or ligands, within a central cavity called a calyx. It has been proposed that these ligands may promote allergic sensitization.
To provide more information on possible lipocalin ligands, the researchers determined crystal structures and conducted structure-function studies for the dog allergen Can f 1 and the closely related cat allergen Fel d 7. Structural comparisons with other lipocalins revealed that Can f 1 and Fel d 7 calyxes are open and positively charged, whereas other dog lipocalin allergens are closed and negatively charged. The results also showed that Can f 1 and Fel d 7 bind to multiple ligands, with preferences for palmitic acid among saturated fatty acids and oleic acid among unsaturated ones.
Taken together, the results reveal potential classes of fatty-acid ligands that bind to two important pet lipocalins. This follows a common trend: more than half of major allergens are known to bind fat soluble molecules, just like the fatty acids described here that bind to Can f 1 and Fel d 7. More research is needed to understand how these ligands affect allergy sensitization in cellular and animal models.
Citation: Min J, Foo ACY, Gabel SA, Perera L, DeRose EF, Pomés A, Pedersen LC, Mueller GA. 2023. Structural and ligand binding analysis of the pet allergens Can f 1 and Fel d 7. Front Allergy 4:1133412.
Rodent flame-retardant results may translate to human lung cancers
Rodents that inhale antimony trioxide develop lung tumors that harbor mutations in genes associated with human lung cancers, according to researchers from the NIEHS Division of Translational Toxicology.
Antimony trioxide is used as a flame retardant in fabrics and plastics. Occupational exposure among miners and smelters occurs mainly through inhalation and skin contact. In rodents, chronic inhalation of antimony trioxide particles results in an increase in the incidence of lung cancers called alveolar/bronchiolar carcinomas (ABCs). In humans, lung cancers are commonly caused by mutations in genes such as KRAS and EGFR, which are both major components of the mitogen-activated protein kinase (MAPK) signaling pathway.
To better understand the translational relevance of rodent tumors to human lung cancers, the researchers examined hotspot mutations in Kras and Egfr in ABCs resulting from chronic inhalation of antimony trioxide for two years. The results revealed Kras and Egfr hotspot mutations in mouse lung tumors, and only Egfr mutations in rat lung tumors. In addition, the global gene expression experiments demonstrated the activation of MAPK signaling in ABCs harboring mutations in Kras and Egfr. Collectively, the findings suggest that chronic exposure to antimony trioxide exacerbates MAPK signaling in ABCs and may be translationally relevant to human lung cancers.
Citation: Ton TT, Hong HL, Kovi RC, Shockley KR, Peddada SD, Gerrish KE, Janardhan KS, Flake G, Stout MD, Sills RC, Pandiri AR. 2023. Chronic inhalation exposure to antimony trioxide exacerbates the MAPK signaling in alveolar bronchiolar carcinomas in B6C3F1/N Mice. Toxicol Pathol; doi: 10.1177/01926233231157322 [Online 3 April 2023]
(Janelle Weaver, Ph.D., is a contract writer for the NIEHS Office of Communications and Public Liaison.)