Papers of the Month
By Cassandra Hayne, Mimi Huang, Florencia Pascual, Victoria Placentra, Prashant Rai
Environmental chemicals and cardiotoxicity
Researchers from the Division of the National Toxicology Program identified several pharmaceutical drugs and environmental chemicals that have cardiotoxic potential based on patterns of activity observed in in vitro assays.
Cardiovascular (CV) disease, the leading cause of death in the United States, is a major public health concern. Lifestyle and genetic predisposition are well established risk factors for CV disease. The contribution of environmental chemicals to CV disease burden is less well-studied. Many assessments of environmental chemical hazards are performed in animal models, which are functionally different from the human CV system.
To overcome this limitation, this study precisely defined six modes of CV failure and their molecular targets. Then, researchers harnessed data available from programs like Toxicology Testing in the 21st Century(https://ntp.niehs.nih.gov/whatwestudy/tox21/) (Tox21) and EPA’s Toxicity Forecaster (ToxCast). By profiling the Tox21/ToxCast chemical library for cardiotoxicity and focusing on in vitro high throughput screening assays, investigators identified several drugs and chemicals with bioactivity against the molecular targets of CV failure modes.
This analysis revealed environmental chemicals that were active at concentrations lower than those toxic to cells. The researchers used structural profiling to identify clusters of chemicals enriched for bioactivity. The study provides a novel approach that combines in vitro and in silico models for identifying and prioritizing chemicals for further cardiotoxicity testing. (VP)
Citation: Krishna S, Berridge B, Kleinstreuer N. 2020. High-throughput screening to identify chemical cardiotoxic potential. Chem Res Toxicol; doi: 10.1021/acs.chemrestox.0c00382 [Online 21 December 2020].
Progesterone receptor promotes ovarian cancer
NIEHS scientists and their collaborators have developed a mouse model of ovarian tumors by overproducing the receptor for the hormone progesterone. The study showed that an imbalance in production of a specific form of progesterone receptor (PGR) can cause uncontrolled cell growth that leads to ovarian cancer.
The animal model is based on targeted expression in the uterus of mice of a progesterone receptor called PGRB. The team reported that overproduction of PGRB resulted in activation of signaling pathways that aid in cell proliferation and increased expression of genes involved in transition of cellular states during proliferation.
Importantly, use of a small-molecule inhibitor against PGRB dramatically reduced abnormal cell growth, induced death in cancerous cells and prevented ovary tumor formation overall. In addition to defining a unique role of progesterone receptor in cancer formation, the authors also showed that the animal tumor model bears molecular signatures specific to human endometrial and ovarian cancer, thus providing insights for the development of uterine cancer in humans. (PR)
Citation: Wetendorf M, Li R, Wu SP, Liu J, Creighton CJ, Wang T, Janardhan KS, Willson CJ, Lanz RB, Murphy BD, Lydon JP, DeMayo FJ. 2020. Constitutive expression of progesterone receptor isoforms promotes the development of hormone-dependent ovarian neoplasms. Sci Signal 13(652):eaaz9646. (Story)
Short sleep, apnea-specific hypoxia linked to kidney disease
Researchers at NIEHS led a team that reported that short sleep and apnea-specific hypoxia, which is the lack of adequate oxygen as a result of apnea, are associated with chronic kidney disease (CKD) in a multi-ethnic population. The findings indicate that sleep disturbance was twice as prevalent among African American participants with CKD compared with white participants. This research is important because it incorporates novel, more sensitive assessments of sleep apnea and evaluates these associations in a racially and ethnically diverse population. Such data is currently lacking in the literature.
Specifically, NIEHS researchers and their collaborators identified very short sleep (five or fewer hours per night) and sleep apnea-specific hypoxia to be associated with moderate-to-severe CKD. These sleep deficiencies may contribute to CKD by worsening known risk factors, such as dyslipidemia, hypertension, and type 2 diabetes. For example, the intermittent hypoxia caused during sleep apnea may increase the generation of reactive oxygen species, promoting inflammation and endothelial dysfunction, which could all lead to hypertension — a strong risk factor for CKD. The association between sleep deficiencies and CKD identifies two specific sleep disturbances that could be targeted by clinicians and public health professionals to help prevent or delay the condition and address health disparities. (MH)
Citation: Jackson CL, Umesi C, Gaston SA, Azarbarzin A, Lunyera J, McGrath JA, Jackson WB, Diamantidis CJ, Boulware E, Lutsey PL, Redline S. 2020. Multiple, objectively measured sleep dimensions including hypoxic burden and chronic kidney disease: findings from the Multi-Ethnic Study of Atherosclerosis. Thorax; doi:10.1136/thoraxjnl-2020-214713 [Online 4 December 2020].
Injectable contraceptive linked to higher lead in blood
Use of the injectable contraceptive depot medroxyprogesterone acetate (DMPA) is associated with increased systemic exposure to the toxic metal lead, according to research from NIEHS scientists and their collaborators. This report is the first to confirm this association with DMPA use among African American women in their 20s and 30s.
Worldwide use of injectable contraceptives has increased four-fold in the past 25 years. DMPA has been used by 20% of sexually active women in the U.S., with higher use among African American women. Using data from the Study of Environment, Lifestyle and Fibroids (SELF), a large study of young African American women, researchers categorized participants as current DMPA users or non-users. Lead was quantified in blood samples collected at enrollment.
The association between DMPA use and blood lead levels was assessed by statistical analyses that adjusted for effects of other factors that can alter blood lead levels, including age, smoking, alcohol use, education, and recent birth. Their results indicate that current DMPA use is linked to 18% higher blood lead levels. According to the authors, these findings identify DMPA use as a contributing factor to blood lead levels and call for a better understanding of its public health impact. (FP)
Citation: Upson K, Harmon QE, Heffron R, Hall JE, Wise LA, Wegienka G, Tokar EJ, Baird DD. 2020. Depot medroxyprogesterone acetate use and blood lead levels in a cohort of young women. Environ Health Perspect 128(11):117004.
Disruption of smooth muscle LRP1 affects lung function in mice
Previously, NIEHS researchers using human genome-wide association studies (GWAS) reported that variations in numerous genes were associated with differences in lung function in humans. Among the first genes identified was low-density lipoprotein receptor-related protein 1(LRP1). Because GWAS does not prove whether associated genes cause the changes, they studied LRP1 in a mouse model.
Removal of LRP1 is lethal to mice, so the researchers developed a mouse model removing LRP1 from a specific cell type: smooth muscle. Examining lung function in these mice, they found increased airway responsiveness and a change in baseline lung function measures, similar to the human data. The researchers also compared responses to two environmental immune stressors, a bacterial substance that activates immune response and household dust mite extract. Responses did not differ between mice with and without LPR1, suggesting that LRP1 does not affect the immune response. They also identified differences in various proteins in lung fluid between mice with and without LRP1.
These findings are especially important because they provide data to support the link between LRP1 and lung function found in GWAS studies. Furthermore, the data supports the use of animal models to analyze lung function changes identified in human GWAS studies. (CH)
Citation: Nichols CE, House JS, Li H, Ward JM, Wyss A, Williams JG, Deterding LJ, Bradbury JA, Miller L, Zeldin DC, London SJ. 2020. Lrp1 regulation of pulmonary function: follow-up of human GWAS in mouse. Am J Respir Cell Mol Biol; doi: 10.1165/rcmb.2019-0444OC [Online 8 December 2020].
(Cassandra Hayne, Ph.D., is an Intramural Research Training Award [IRTA] fellow in the NIEHS Nucleolar Integrity Group. Mimi Huang, Ph.D., is an IRTA fellow in the Division of the National Toxicology Program (DNTP) Systems Toxicology Group. Florencia Pascual, Ph.D., is a scientist in the NIEHS Pediatric Neuroendocrinology Group. Victoria Placentra is an 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.)