Papers of the Month
By Rachel Carroll, Yu-Wei Chen, Samantha Hall, Gabriel Knudsen, and Emily Mesev
NTP finds mice given black cohosh produce altered red blood cells
National Toxicology Program (NTP) researchers recently demonstrated that black cohosh dried ethanolic extract (BCE) resulted in dyserythropoiesis, or defective red blood cell (RBC) production, in mice. BCE is a dietary supplement frequently used as a remedy for menopausal symptoms and pain during menstruation. A 90-day subchronic study conducted by NTP showed a dose-dependent increase in macrocytic, or large size, RBCs in conjunction with a decrease in RBC counts, hemoglobin concentration, and hematocrit, indicative of megaloblastic-type anemia. In humans, megaloblastic anemia is often attributed to folate or cobalamin, also known as vitamin B12 deficiencies. This study investigated whether these deficiencies were related to the observed hematopoietic toxicity of BCE.
The researchers found that while circulating folate and cobalamin levels were not different between control and dosed B6C2F1/N female mice, homocysteine and methylmalonic acid (MMA) were both elevated in blood samples. In addition, significant increases in the number of Howell-Jolly bodies were present in RBCs, which suggested chromosomal damage and RBC basophilic stippling, which are often associated with abnormal production of erythrocytes. The authors concluded that BCE administration caused biochemical and hematological changes that were consistent with a functional, but not absolute, cobalamin deficiency. Future studies will evaluate hematological changes in bone marrow related to observed increases in homocysteine and MMA. (GK)
Cora MC, Gwinn W, Wilson R, King D, Waidyanatha S, Kissling GE, Brar SS, Olivera D, Blystone C, Travlos G. 2017. A black cohosh extract causes hematologic and biochemical changes consistent with a functional cobalamin deficiency in female B6C3F1/N mice. Toxicol Pathol; doi: 10.1177/0192623317714343 [Online 15 June 2017].
SIRT1 regulates intestinal inflammation through microbiome
Researchers reported that SIRT1, a key repressor of inflammation, regulates inflammation in the intestines by altering intestinal microbiota. SIRT1 modulates epithelial homeostasis in the intestines. Disruption of this homeostasis leads to disorders such as inflammatory bowel disease (IBD).
The scientists established mice with a deletion of SIRT1 in the intestinal epithelium. The intestinal SIRT1 knockout mice developed more spontaneous inflammation in the intestine than control mice. Furthermore, the SIRT1 knockout mice also had altered fecal microbiota, and less species richness and diversity in their gut bacteria. The gut microbiome affects nutrient metabolism and the immune system. Disrupting the gut microbiome can lead to disease.
SIRT1 has a direct effect on a specific bacterial group called Lactobacillus, in part, through regulation of bile acid metabolism. IBD patients have reduced Lactobacillus in their gut, and the SIRT1 knockout mice in this study also had reduced Lactobacillus. Based on this research, the scientists theorized that SIRT1 is critical for preventing intestinal inflammation by mediating host-microbiome interactions, especially Lactobacillus. Medications that activate intestinal SIRT1 could therefore have potential as treatments for IBDs. (SH)
Wellman AS, Metukuri MR, Kazgan N, Xu X, Xu Q, Ren NSX, Czopik A, Shanahan MT, Kang A, Chen W, Azcarate-Peril MA, Gulati AS, Fargo DC, Guarente L, Li X. 2017. Intestinal epithelial Sirtuin 1 regulates intestinal inflammation during aging in mice by altering the intestinal microbiota. Gastroenterology; doi: 10.1053/j.gastro.2017.05.022 [Online 25 May 2017].
Uterine responses in the absence of estrogen receptor alpha
NIEHS scientists found that insulin-like growth factor 1 (IGF1) can signal both dependently and independently of estrogen receptor alpha (ER-alpha) in the uterus, which leads to different uterine responses. The study found that IGF1 appears to require ER-alpha for biological responses of the uterus, but does not require it for many transcriptional responses.
In the rodent uterus, estrogen (E2) signals through ER-alpha to trigger proliferation of epithelial cells. Because deletion of epithelial ER-alpha does not prevent E2 from inducing epithelial cell growth, this effect is thought to occur in a paracrine manner, which means it acts on nearby cells, via stromal ER-alpha.
The current study found that an ER-alpha antagonist inhibited the action of E2 treatment, but did not hinder IGF1 from inducing uterine epithelial cell growth, which suggested that the presence of ER-alpha is dispensable for IGF1-mediated uterine growth. Selective deletion of ER-alpha in the uterus inhibited the production of E2-induced transcripts, but not the induction of many of the same transcripts by IGF1.
Using Chip-seq, the researchers found that IGF1 treatment, like E2, increased ER-alpha recruitment to chromatin. Transcriptional profiles showed that IGF1 can also activate a number of responses independently of ER-alpha. The data implicate IGF1 in paracrine signaling that affects uterine growth and overall reproductive health. (EM)
Hewitt SC, Winuthayanon W, Lierz SL, Hamilton KJ, Donoghue LJ, Ramsey JT, Grimm SA, Arao Y, Korach KS. 2017. Role of ERalpha in mediating female uterine transcriptional responses to IGF1. Endocrinology; doi: 10.1210/en.2017-00349. [Online 6 June 2017].
Ovarian reserve marker lower in women exposed to indoor air pollutants
NIEHS researchers and collaborators found that exposure to tobacco smoke and indoor air pollutants from some stove and fireplace fuels may have a negative impact on women's reproductive health. Cigarette smoking and burning fuels for heating or cooking both produce polycyclic aromatic hydrocarbons, a combustion byproduct known to impair human health. However, few studies have investigated the effect of these household air pollutants on reproductive function.
The researchers conducted a cross-sectional analysis that involved 913 premenopausal women enrolled in the Sister Study who provided blood samples and questionnaire data on their use of tobacco, exposure to cigarette smoke from others, and residential heating and cooking fuels. The researchers examined associations between serum levels of antimullerian hormone (AMH), a biomarker of ovarian reserve, and environmental exposure histories. AMH levels increase in girls up to age 20 and then decline gradually until menopause. AMH can therefore be considered an overall indicator of reproductive capacity.
After adjusting for variables such as age, parity and breastfeeding history, race, education, and household income, lower AMH levels, which indicate reduced ovary function, were observed in women who were current smokers and those who were exposed to environmental tobacco smoke for more than 10 years. Lower AMH levels were also associated with burning wood or artificial fire logs indoors, raising the possibility of toxic effects of those common household practices on the reproductive system. (YWC)
White AJ, Sandler DP, D’Aloisio AA, Stanczyk F, Whitworth KW, Baird DD, Nichols HB. 2017. Antimullerian hormone in relation to tobacco and marijuana use and sources of indoor heating/cooking. Fertil Steril 106(3):723−730.
Team finds novel DNA methylation sites associated with COPD
An international team of Korean and NIEHS researchers identified locations of genetic modifications related to lung disease and lung function. Specifically, they examined DNA methylation, which is the addition of methyl groups to DNA.
Most previous studies have been done in populations of European ancestry. The authors measured DNA methylation in blood from a Korean cohort with chronic obstructive pulmonary disease (COPD) using a commercial array, Illumina HumanMethylation450 or 450K technology. They examined both COPD and tests of pulmonary function. The authors performed analyses both at the level of individual sites of the DNA, called CpGs, and regions of the DNA. They found novel associations at one individual CpG site and 104 regions.
The scientists evaluated lung function and COPD status among the cohort. Using information from DNA methylation, the authors used statistical methods to examine the relationship between methylation values and pulmonary traits. The results showed evidence of an association between one site and 104 regions. Using gene expression data from another Korean cohort, the authors found that for 34 of the genes in these regions, expression was related to the same trait that was found to be differentially methylated. Pathway analyses highlighted fundamental developmental pathways. It is possible that methylation could contribute to the pathogenesis of reduced lung function and COPD. (RC)
Lee MK, Hong Y, Kim SY, Kim WJ, London SJ. 2017. Epigenome-wide association study of chronic obstructive pulmonary disease and lung function in Koreans. Epigenomics 9(7):971−984.
(Rachel Carroll, Ph.D., is a research fellow in the NIEHS Biostatistics and Computational Biology Branch. Yu-Wei Chen, Ph.D., is a research fellow in the NIEHS Developmental Neurobiology Group. Samantha Hall is a postbaccalaureate Intramural Research and Training Award (IRTA) fellow in the National Cancer Institute, Center for Cancer Research, Laboratory of Toxicology and Toxicokinetics. Gabriel Knudsen, Ph.D., is a Cancer Research Training Award fellow in the National Cancer Institute, Center for Cancer Research, Laboratory of Toxicology and Toxicokinetics. Emily Mesev is a postbaccalaureate IRTA fellow in the NIEHS Intracellular Regulation Group.)