Papers of the Month
By Kelley Christensen, Ernie Hood, Victoria Placentra, and Janelle Weaver
DNTP finds pain relievers do not impair or delay wound healing in mice
Researchers from the Division of the National Toxicology Program (DNTP) analyzed whether three pain reducers slow wound healing in laboratory mice. The scientists discovered that opioid analgesic buprenorphine, topical antiseptic chlorhexidine, and low-level laser therapy (LLLT) do not slow or alter the mouse’s healing process.
Buprenorphine, chlorhexidine, and LLLT are frequently used in research animals to aid in pain control and to reduce infection. Although other studies have in the past provided conflicting data that the three pain relievers delay wound healing, the NIEHS researchers found no significant differences in the rate of wound closure.
The scientists conducted two studies, both of which used mice that were either treated with a single injection of buprenorphine or saline, prior to wounding by either punch biopsy or dermal abrasion. In the first study, of the 20 wounded mice, half of the saline group and half of the buprenorphine group were then treated with chlorhexidine. In the second study, conducted in two equal batches, the 90 wounded mice were separated into treatment groups of combinations of the pain relievers or just saline. The researchers used Image J software to longitudinally analyze the wound area.
Wound healing is a complex physiological process and animal research has been used to develop a better understanding of its mechanisms. (KC)
Citation: Webb DR, Churchill SR, Hill GD, McGee CA, Shi M, King-Herbert AP, Blankenship-Paris TL. 2021. Effects of buprenorphine, chlorhexidine, and low-level laser therapy on wound healing in mice. Comp Med 71(3):191–202.
A molecular cascade shapes the fate of stem cells
NIEHS researchers have revealed how a protein called INO80 controls the fate of stem cells. INO80 is involved in many cellular and developmental processes, as well as neurological diseases and cancer. As a chromatin remodeler, INO80 can regulate gene activity by altering the structure of chromatin, which is a substance consisting of DNA and proteins such as histones. The study provided new insights into the functions of INO80 in pluripotent stem cells, which can give rise to all cell types in the body.
The researchers inactivated the INO80 gene in mouse stem cells at different developmental stages. The results showed that INO80 enhances the binding of a histone variant called H2A.Z to key DNA sequences at the later developmental stage. This event triggers the addition of certain chemical groups to histones, thereby decreasing the activity of nearby genes that play important roles in development.
Taken together, the findings revealed unexpected functions of INO80 in regulating the genomic positioning of H2A.Z and gene activity. Because INO80 and H2A.Z have been heavily implicated in development and disease, this molecular pathway may play a similar role in controlling cell fate across diverse biological contexts. (JW)
Citation: Yu H, Wang J, Lackford B, Bennett B, Li JL, Hu G. 2021. INO80 promotes H2A.Z occupancy to regulate cell fate transition in pluripotent stem cells. Nucleic Acids Res 49(12):6739–6755.
SIRT1 regulation of sphingolipid metabolism may offer therapeutic target
An international collaboration led by NIEHS scientists identified a previously unknown molecular mechanism that when perturbed may contribute to human neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and Huntington’s.
The research focused on sphingolipids, types of lipids that help to make up the structure of cell membranes. Sphingolipids are particularly abundant in the brain and help regulate cell growth, differentiation, and apoptosis. Other studies have found that defects in sphingolipid degradation are associated with human neurodegenerative diseases.
Using mouse embryonic stem cells, the authors found that the protein SIRT1 exercises transcriptional control of sphingolipid degradation. The research suggests that the previously uncharacterized transcriptional regulation of SIRT1 on sphingomyelin degradation links cellular levels of sphingomyelin and membrane fluidity with cellular energy status. That link provides a possible molecular mechanism for the benefits of SIRT1 small molecule activators and nicotinamide adenine dinucleotide dietary supplements on human neurodegenerative diseases. Pharmacological activation of SIRT1 by those agents may also positively affect maternal obesity-associated neonatal complications and defective childhood neurodevelopment. (EH)
Citation: Fan W, Tang S, Fan X, Fang Y, Xu X, Li L, Xu J, Li JL, Wang Z, Li X. 2021. SIRT1 regulates sphingolipid metabolism and neural differentiation of mouse embryonic stem cells through c-Myc-SMPDL3B. Elife 10:e67452.
Frequent use of hair products linked to increased ovarian cancer risk
A team of NIEHS researchers found that frequent use of certain hair products is linked to an increased risk of ovarian cancer. Previous research has linked use of some hair products to breast cancer, but research on ovarian cancer is limited.
Many commonly used hair products contain chemicals that are carcinogens or endocrine disruptors that can be absorbed into the blood stream. The researchers used data from the Sister Study(https://sisterstudy.niehs.nih.gov/English/index1.htm), which included approximately 40,000 women who had not had their ovaries removed before joining the study. The women completed questionnaires about their hair product use in the year prior to enrollment and continued to provide updates about their health during approximately 10 years of follow-up.
The scientists found that use of hair dyes, bleaches, and perms in the year before enrollment was not associated with ovarian cancer risk overall. However, frequent use of relaxers or straightening/pressing products, defined as use more than four times per year, was linked to an increased risk of ovarian cancer. Further, permanent hair dye use was associated with risk for non-serous type tumors. The findings have important public health implications, especially for African-American and Black women, who more often use chemical hair straighteners or relaxers. (VP)
Citation: White AJ, Sandler DP, Gaston SA, Jackson CL, O'Brien KM. 2021. Use of hair products in relation to ovarian cancer risk. Carcinogenesis; doi: 10.1093/carcin/bgab056 [Online 26 June 2021].
Single-cell data shed light on genitalia formation
NIEHS researchers have provided new insights into the cell populations and hormones that orchestrate genitalia development. Among the most common birth defects worldwide are those that affect the external genitalia. Yet the underlying causes of 70% of genitalia birth defects remain unknown. Addressing this knowledge gap requires more information about hormone signaling and the tight coordination among neighboring cells in the embryo as genitalia form.
Toward this goal, the researchers used single-cell messenger RNA sequencing in mouse embryos at critical developmental stages. Overall, the external genitalia in males and females were largely similar in cell composition and gene activity at the earliest stage. Subsequently, males and females showed genetic differences in key developmental pathways. This resulted in distinct cellular responses to the sex hormones androgen and estrogen, even though the cell populations were still highly similar in males and females. By the last stage, differences in cell populations eventually arose, leading to sex-specific external genitalia.
The findings suggest that the sex hormones help to synchronize various cell populations as they carry out unique roles in genitalia formation. According to the researchers, the study could lead to a better understanding of diseases associated with defects in the external genitalia, potentially paving the way for more effective treatment strategies. (JW)
Citation: Amato CM, Yao HH. 2021. Developmental and sexual dimorphic atlas of the prenatal mouse external genitalia at the single-cell level. Proc Natl Acad Sci U S A 118(25):e2103856118. Story
(Kelley Christensen is a contract writer and editor for the NIEHS Office of Communications and Public Liaison. Ernie Hood is a contract writer for the NIEHS Office of Communications and Public Liaison. Victoria Placentra is an Intramural Research Training Award postbaccalaureate fellow in the NIEHS Mutagenesis and DNA Repair Regulation Group. Janelle Weaver, Ph.D., is a contract writer for the NIEHS Office of Communications and Public Liaison.)