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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 289 records · Page 16
All sourcesNASA NTRSDOE OSTI
DOE OSTI2018

Two different restriction-modification systems for degrading exogenous DNA in Paenibacillus polymyxa

Highlights: • Dam methylated DNA from E. coli is strongly restricted in P. polymyxa. • DNA without Dam methylation is moderately restricted in P. polymyxa. • P. polymyxa is equipped with DNA-methylation-dependent and -independent R-M systems. • Genetic manipulation tools in P. polymyxa. Accompanied by benefits from horizontally transferred genes, bacteria have to face the risk of the invasion of dangerous genes. Bacteria often use the restriction-modification (R-M) system, which is consisted of methyl transferase (MEase) and restrictase (REase), to protect self-DNA and defend against foreign DNA. Paenibacillus polymyxa, widely used as growth promoting rhizobacteria in agriculture, can also produce compounds of medical and industrial interests. It is unclear whether R-M systems exist in P. polymyxa. In this study, we used a shuttle plasmid with epigenetic modification from different bacteria to explore R-M systems in P. polymyxa. We found that DNA which is methylated by DNA adenine methyltransferase (Dam) in E. coli was strongly restricted, indicating the presence of a Dam-methylation-dependent R-M system in P. polymyxa. Whereas, DNA from a dam{sup -} E. coli strain was also moderately restricted, indicating the presence of a Dam-methylation-independent R-M system. Degradation of plasmid DNA with Dam methylation by cell-free protein extract of P. polymyxa provides additional evidence for the presence of Dam-methylation-dependent R-M system. Taken together, our work showed that there are two different types of R-M system in P. polymyxa, providing a foundation for the study of innate immunity in P. polymyxa and for the development of genetic engineering tools in P. polymyxa.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

MiR-326 antagomir delays the progression of age-related cataract by upregulating FGF1-mediated expression of betaB2-crystallin

Highlights: • FGF-1 upregulates the expression of an anti-cataract protein βB2. • miR-326 inhibits FGF-1 expression and thereby decreases βB2 level. • miR-326 antagomir delay cataract progression via the function of miR-326. Age-related cataract, the most common cause of blindness worldwide, has been found closely associated with β-crystallin B2 (βB2 or CRYBB2). MicroRNAs (miRNAs) are the primary epigenetic regulators important for various biological processes. However, the role of miRNAs in the progression of lens cataract remains to be elucidated. In this study, we found a novel signal cascade miR-326–fibroblast growth factor 1 (FGF1)–βB2 modulating the progression of lens cataract. In brief, miR-326 exacerbated but its antagomirs attenuated H{sub 2}O{sub 2}-induced apoptosis of HLEC-B3 human lens epithelial cells. Dual-luciferase reporter assay and Western blot showed that miR-326 inhibited FGF1 expression by directly targeting its mRNA 3′-UTR. Consistent with this result, miR-326 antagomir enhanced FGF1 protein level. In addition to FGF1, miR-326 antagomir also enhanced βB2 expression and this enhancement was abolished by transfection of HLEC-B3 cells with FGF1 shRNA. These data demonstrated that miR-326 antagomir increased βB2 expression via upregulating FGF1, which was further confirmed by the studies in a rat model of selenite-induced cataract. This work suggests that miR-326 antagomir might be a promising candidate to prevent progression of age-related cataract.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Protective effect of electro-acupuncture at maternal different points on perinatal nicotine exposure-induced pulmonary dysplasia in offspring based on HPA axis and signal transduction pathway

Perinatal nicotine exposure can not only lead to lung dysplasia in offspring, but also cause epigenetic changes and induce transgenerational asthma. Previous studies have shown that electro-acupuncture (EA) applied to “Zusanli” (ST 36) can improve the lung morphology and correct abnormal expression of lung development-related protein in perinatal nicotine exposure offspring. However, it is still unclear whether ST 36 has a specific therapeutic effect and how maternal acupuncture can protect the offspring from pulmonary dysplasia. In this study, we compared the different effect of ST 36 and “Fenglong” (ST 40), which belong to the same meridian, in terms of lung pulmonary function and morphology, PPARγ, β-catenin, GR levels in the lung tissues and CORT in the serum of perinatal nicotine exposure offspring, and explored the mechanism of acupuncture based on the maternal hypothalamus-pituitary-adrenal (HPA) axis. It is shown that EA applied to ST 36 could restore the normal function of maternal HPA axis and alleviate maternal glucocorticoid overexposure in offspring, thereby it can up-regulate the PTHrP/PPARγ and down-regulate the Wnt/β-catenin signaling pathways, and protects perinatal nicotine exposure-induced pulmonary dysplasia in offspring. Its effect is better than that of ST 40. These results are of great significance in preventing perinatal nicotine exposure-induced pulmonary dysplasia in offspring.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Multiomic Network Analysis Identifies Dysregulated Neurobiological Pathways in Opioid Addiction

BACKGROUND: Opioid addiction is a worldwide public health crisis. In the United States, for example, opioids cause more drug overdose deaths than any other substance. However, opioid addiction treatments have limited efficacy, meaning that additional treatments are needed. METHODS: To help address this problem, we used network-based machine learning techniques to integrate results from genome-wide association studies of opioid use disorder and problematic prescription opioid misuse with transcriptomic, proteomic, and epigenetic data from the dorsolateral prefrontal cortex of people who died of opioid overdose and control individuals. RESULTS: Here we identified 211 highly interrelated genes identified by genome-wide association studies or dysregulation in the dorsolateral prefrontal cortex of people who died of opioid overdose that implicated the Akt, BDNF (brain-derived neurotrophic factor), and ERK (extracellular signal-regulated kinase) pathways, identifying 414 drugs targeting 48 of these opioid addiction–associated genes. Some of the identified drugs are approved to treat other substance use disorders or depression. CONCLUSIONS: Our synthesis of multiomics using a systems biology approach revealed key gene targets that could contribute to drug repurposing, genetics-informed addiction treatment, and future discovery.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Pan-cancer proteogenomics characterization of tumor immunity

Despite the successes of immunotherapy in cancer treatment over recent decades, less than <10%–20% cancer cases have demonstrated durable responses from immune checkpoint blockade. To enhance the efficacy of immunotherapies, combination therapies suppressing multiple immune evasion mechanisms are increasingly contemplated. To better understand immune cell surveillance and diverse immune evasion responses in tumor tissues, we comprehensively characterized the immune landscape of more than 1,000 tumors across ten different cancers using CPTAC pan-cancer proteogenomic data. We identified seven distinct immune subtypes based on integrative learning of cell type compositions and pathway activities. We then thoroughly categorized unique genomic, epigenetic, transcriptomic, and proteomic changes associated with each subtype. Further leveraging the deep phosphoproteomic data, we studied kinase activities in different immune subtypes, which revealed potential subtype-specific therapeutic targets. Insights from this work will facilitate the development of future immunotherapy strategies and enhance precision targeting with existing agents.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Structural Basis for KDM5A Histone Lysine Demethylase Inhibition by Diverse Compounds

The KDM5/JARID1 family of Fe(II)- and α-ketoglutarate-dependent demethylases removes methyl groups from methylated lysine 4 of histone H3. Accumulating evidence supports a role for KDM5 family members as oncogenic drivers. In this work, we compare the in vitro inhibitory properties and binding affinity of ten diverse compounds with all four family members, and present the crystal structures of the KDM5A-linked Jumonji domain in complex with eight of these inhibitors in the presence of Mn(II). All eight inhibitors structurally examined occupy the binding site of α-ketoglutarate, but differ in their specific binding interactions, including the number of ligands involved in metal coordination. We also observed inhibitor-induced conformational changes in KDM5A, particularly those residues involved in the binding of α-ketoglutarate, the anticipated peptide substrate, and intramolecular interactions. We discuss how particular chemical moieties contribute to inhibitor potency and suggest strategies that might be utilized in the successful design of selective and potent epigenetic inhibitors.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2015

Infant sex-specific placental cadmium and DNA methylation associations

Background: Recent evidence suggests that maternal cadmium (Cd) burden and fetal growth associations may vary by fetal sex. However, mechanisms contributing to these differences are unknown. Objectives: Among 24 maternal-infant pairs, we investigated infant sex-specific associations between placental Cd and placental genome-wide DNA methylation. Methods: We used ANOVA models to examine sex-stratified associations of placental Cd (dichotomized into high/low Cd using sex-specific Cd median cutoffs) with DNA methylation at each cytosine-phosphate-guanine site or region. Statistical significance was defined using a false discovery rate cutoff (<0.10). Results: Medians of placental Cd among females and males were 5 and 2 ng/g, respectively. Among females, three sites (near ADP-ribosylation factor-like 9 (ARL9), siah E3 ubiquitin protein ligase family member 3 (SIAH3), and heparin sulfate (glucosamine) 3-O-sulfotransferase 4 (HS3ST4) and one region on chromosome 7 (including carnitine O-octanoyltransferase (CROT) and TP5S target 1 (TP53TG1)) were hypomethylated in high Cd placentas. Among males, high placental Cd was associated with methylation of three sites, two (hypomethylated) near MDS1 and EVI1 complex locus (MECOM) and one (hypermethylated) near spalt-like transcription factor 1 (SALL1), and two regions (both hypomethylated, one on chromosome 3 including MECOM and another on chromosome 8 including rho guanine nucleotide exchange factor (GEF) 10 (ARHGEF10). Differentially methylated sites were at or close to transcription start sites of genes involved in cell damage response (SIAH3, HS3ST4, TP53TG1) in females and cell differentiation, angiogenesis and organ development (MECOM, SALL1) in males. Conclusions: Our preliminary study supports infant sex-specific placental Cd-DNA methylation associations, possibly accounting for previously reported differences in Cd-fetal growth associations across fetal sex. Larger studies are needed to replicate and extend these findings. Such investigations may further our understanding of epigenetic mechanisms underlying maternal Cd burden with suboptimal fetal growth associations. - Highlights: • We examine sex-specific placental-Cd and -genome-wide DNA methylation associations. • In females, associated sites were at/near genes involved in cell damage response. • In males, associated sites were at/near angiogenesis and organ development genes. • Our study supports infant sex-specific placental Cd-DNA methylation associations.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Microbial influences on hormesis, oncogenesis, and therapy: A review of the literature

Utilization of environmental stimuli for growth is the main factor contributing to the evolution of prokaryotes and eukaryotes, independently and mutualistically. Epigenetics describes an organism’s ability to vary expression of certain genes based on their environmental stimuli. The diverse degree of dose-dependent responses based on their variances in expressed genetic profiles makes it difficult to ascertain whether hormesis or oncogenesis has or is occurring. In the medical field this is shown where survival curves used in determining radiotherapeutic doses have substantial uncertainties, some as large as 50% (Barendsen, 1990). Many in-vitro radiobiological studies have been limited by not taking into consideration the innate presence of microbes in biological systems, which have either grown symbiotically or pathogenically. Present in-vitro studies neglect to take into consideration the varied responses that commensal and opportunistic pathogens will have when exposed to the same stimuli and how such responses could act as stimuli for their macro/microenvironment. As a result many theories such as radiation carcinogenesis explain microscopic events but fail to describe macroscopic events (Cohen, 1995). As such, this review shows how microorganisms have the ability to perturb risks of cancer and enhance hormesis after irradiation. It will also look at bacterial significance in the microenvironment of the tumor before and during treatment. In addition, bacterial systemic communication after irradiation and the host’s immune responses to infection could explain many of the phenomena associated with bystander effects. Therefore, the present literature review considers the paradigms of hormesis and oncogenesis in order to find a rationale that ties them all together. This relationship was thus characterized to be the microbiome.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Association between fetal exposure to phthalate endocrine disruptor and genome-wide DNA methylation at birth

Highlights: • Humans are ubiquitously exposed to phthalates through digestion, inhalation, or dermal absorption. • DNA methylation has been hypothesized to be an important mechanism in in utero phthalate exposure. • DNA methylation changes are involved in androgen response, estrogen response, protein secretion, and spermatogenesis. • Three CpG sites (cg00935782, cg07732421, and cg00764560) are involved in genes of response to androgen. Phthalic acid esters are ubiquitous and antiandrogenic, and may cause systemic effects in humans, particularly with in utero exposure. Epigenetic modification, such as DNA methylation, has been hypothesized to be an important mechanism that mediates certain biological processes and pathogenic effects of in utero phthalate exposure.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Environmental hormesis and its fundamental biological basis: Rewriting the history of toxicology

Highlights: • Autophagy is activated in the framework of hormesis. • Low doses of stressors promote health and extend lifespan. • Health can be maximized via calorie restriction and intermittent fasting. • Hormesis can protect against aging diseases and exogenous environmental stresses. • Hormesis provides a perspective for enhancing community health and patient success. It has long been debated whether a little stress may be “good” for you. Extensive evidence has now sufficiently accumulated demonstrating that low doses of a vast range of chemical and physical agents induce protective/beneficial effects while the opposite occurs at higher doses, a phenomenon known as hormesis. Low doses of environmental agents have recently induced autophagy, a critical adaptive response that protects essentially all cell types, as well as being transgenerational via epigenetic mechanisms. These collective findings highlight a generalized and substantial ongoing dose-response transformation with significant implications for disease biology and clinical applications, challenging the history and practice of toxicology and pharmacology along with an appeal to stake holders to reexamine the process of risk assessment, with the goal of optimizing public health rather than simply avoiding harm.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2024

Antimony stable isotope fractionation during adsorption onto birnessite: A molecular perspective from X-ray absorption spectroscopy and density functional theory

Sorption of antimony (Sb) onto birnessite significantly influences the fate of Sb in oceanic and terrestrial environments and fractionates Sb isotopes. Nevertheless, little is known about Sb isotopic fractionation during its adsorption on birnessite. Here, in this study, we show the value of Δ 123 Sb adsorbed-aqueous increases from −0.398 to −0.332 ‰ in 1 h and then decreases and stabilizes at −0.384 ‰ in 72 h. The enrichment of the light Sb isotope is predominantly due to the distortion of the octahedral symmetry. X-ray absorption spectroscopy results indicate Sb first forms a double-corner-sharing complex on birnessite and then transforms to a double-edge-sharing complex during adsorption. The optimized bond distances for double-corner-sharing (3.37 Å) and double-edge-sharing (2.90 Å) complexes calculated using density functional theory (DFT) fits well with the structure (3.41 and 3.00 Å) revealed by X-ray absorption spectroscopy, respectively. The fractionation derived from reduced partition function ratios calculated using DFT aligns well with the experimental results. Therefore, the variation in Sb isotopic fractionation during adsorption is attributed to the evolving structure of Sb complexes on birnessite. Our results demonstrate the isotopic fractionation of Sb during adsorption on birnessite and provide a molecular-scale understanding of Sb behavior, contributing to the correct reconstruction of the Sb isotope composition of ancient seawater using ferromanganese crusts and nodules, and efforts to trace Sb migration in epigenetic mining environments.

Adsorption↗
DOE OSTI2020

X-Ray Fluorescence Microscopy: A Method of Measuring Ion Concentrations in the Ear

This technical note describes synchrotron x-ray fluorescence microscopy (XFM) as a method for measuring the concentrations of various elements in cross-sections of the ear at extremely high resolution. This method could be of great importance for addressing many open questions in hearing research. XFM uses synchrotron radiation to evoke emissions from many biologically relevant elements in the tissue. The intensity and wavelength of the emitted radiation provide a fingerprint of the tissue composition that can be used to measure the concentration of the elements in the sampled location. Here, we focus on energies that target biologically-relevant elements of the periodic table between magnesium and zinc. Since a highly focused x-ray beam is used, the spot size is well below 1 mu m and the samples can be scanned at a nanometer lateral resolution. This study shows that measurement of the concentrations of different elements is possible in a mid-modiolar cross-section of a mouse cochlea. Images are presented that indicate potassium and chloride "hot spots" in the spiral ligament and the spiral limbus, providing experimental evidence for the potassium recycling pathway and showing the cochlear structures involved. Scans of a section obtained from the incus, one of the middle ear ossicles, in a developing mouse have shown that zinc is not uniformly distributed This supports the hypothesis that zinc plays a special role in the process of ossification. Although limited by sophisticated sample preparation and sectioning, the method provides ample exciting opportunities, to understand the role of genetics and epigenetics on hearing mechanisms in ontogeny and phylogeny.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2014

Genetic Susceptibility to Head and Neck Squamous Cell Carcinoma

Head-and-neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and its incidence is growing. Although environmental carcinogens and carcinogenic viruses are the main etiologic factors, genetic predisposition obviously plays a risk-modulating role, given that not all individuals exposed to these carcinogens experience the disease. This review highlights some aspects of genetic susceptibility to HNSCC: among others, genetic polymorphisms in biotransformation enzymes, DNA repair pathway, apoptotic pathway, human papillomavirus-related pathways, mitochondrial polymorphisms, and polymorphism related to the bilirubin-metabolized pathway. Furthermore, epigenetic variations, familial forms of HNSCC, functional assays for HNSCC risk assessment, and the implications and perspectives of research on genetic susceptibility in HNSCC are discussed.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2014

Development of TRAIL Resistance by Radiation-Induced Hypermethylation of DR4 CpG Island in Recurrent Laryngeal Squamous Cell Carcinoma

Purpose: There are limited therapeutic options for patients with recurrent head and neck cancer after radiation therapy failure. To assess the use of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) as a salvage chemotherapeutic agent for recurrent cancer after radiation failure, we investigated the effect of clinically relevant cumulative irradiation on TRAIL-induced apoptosis. Methods and Materials: Using a previously established HN3 cell line from a laryngeal carcinoma patient, we generated a chronically irradiated HN3R isogenic cell line. Viability and apoptosis in HN3 and HN3R cells treated with TRAIL were analyzed with MTS and PI/annexin V-FITC assays. Western blotting and flow cytometry were used to determine the underlying mechanism of TRAIL resistance. DR4 expression was semiquantitatively scored in a tissue microarray with 107 laryngeal cancer specimens. Methylation-specific polymerase chain reaction and bisulfite sequencing for DR4 were performed for genomic DNA isolated from each cell line. Results: HN3R cells were more resistant than HN3 cells to TRAIL-induced apoptosis because of significantly reduced levels of the DR4 receptor. The DR4 staining score in 37 salvage surgical specimens after radiation failure was lower in 70 surgical specimens without radiation treatment (3.03 ± 2.75 vs 5.46 ± 3.30, respectively; P<.001). HN3R cells had a methylated DR4 CpG island that was partially demethylated by the DNA demethylating agent 5-aza-2′-deoxycytidine. Conclusion: Epigenetic silencing of the TRAIL receptor by hypermethylation of a DR4 CpG island might be an underlying mechanism for TRAIL resistance in recurrent laryngeal carcinoma treated with radiation.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2014

Ionizing Radiation–Inducible miR-27b Suppresses Leukemia Proliferation via Targeting Cyclin A2

Purpose: Ionizing radiation is a common carcinogen that is important for the development of leukemia. However, the underlying epigenetic mechanisms remain largely unknown. The goal of the study was to explore microRNAome alterations induced by ionizing radiation (IR) in murine thymus, and to determine the role of IR-inducible microRNA (miRNA/miR) in the development of leukemia. Methods and Materials: We used the well-established C57BL/6 mouse model and miRNA microarray profiling to identify miRNAs that are differentially expressed in murine thymus in response to irradiation. TIB152 human leukemia cell line was used to determine the role of estrogen receptor–α (ERα) in miR-27b transcription. The biological effects of ectopic miR-27b on leukemogenesis were measured by western immunoblotting, cell viability, apoptosis, and cell cycle analyses. Results: Here, we have shown that IR triggers the differential expression of miR-27b in murine thymus tissue in a dose-, time- and sex-dependent manner. miR-27b was significantly down-regulated in leukemia cell lines CCL119 and TIB152. Interestingly, ERα was overexpressed in those 2 cell lines, and it was inversely correlated with miR-27b expression. Therefore, we used TIB152 as a model system to determine the role of ERα in miR-27b expression and the contribution of miR-27b to leukemogenesis. β-Estradiol caused a rapid and transient reduction in miR-27b expression reversed by either ERα-neutralizing antibody or ERK1/2 inhibitor. Ectopic expression of miR-27b remarkably suppressed TIB152 cell proliferation, at least in part, by inducing S-phase arrest. In addition, it attenuated the expression of cyclin A2, although it had no effect on the levels of PCNA, PPARγ, CDK2, p21, p27, p-p53, and cleaved caspase-3. Conclusion: Our data reveal that β-estradiol/ERα signaling may contribute to the down-regulation of miR-27b in acute leukemia cell lines through the ERK1/2 pathway, and that miR-27b may function as a tumor suppressor that inhibits cell proliferation by targeting cyclin A2.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Cardiac Reprogramming Factors Synergistically Activate Genome-wide Cardiogenic Stage-Specific Enhancers

The cardiogenic transcription factors (TFs) Mef2c, Gata4, and Tbx5 can directly reprogram fibroblasts to induced cardiac-like myocytes (iCLMs), presenting a potential source of cells for cardiac repair. While activity of these TFs is enhanced by Hand2 and Akt1, their genomic targets and interactions during reprogramming are not well studied. We performed genome-wide analyses of cardiogenic TF binding and enhancer profiling during cardiac reprogramming. We found that these TFs synergistically activate enhancers highlighted by Mef2c binding sites and that Hand2 and Akt1 coordinately recruit other TFs to enhancer elements. Intriguingly, these enhancer landscapes collectively resemble patterns of enhancer activation during embryonic cardiogenesis. We further constructed a cardiac reprogramming gene regulatory network and found repression of EGFR signaling pathway genes. Consistently, chemical inhibition of EGFR signaling augmented reprogramming. Thus, by defining epigenetic landscapes these findings reveal synergistic transcriptional activation across a broad landscape of cardiac enhancers and key signaling pathways that govern iCLM reprogramming.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Fetal and neonatal exposure to nicotine leads to augmented hepatic and circulating triglycerides in adult male offspring due to increased expression of fatty acid synthase

While nicotine replacement therapy is assumed to be a safer alternative to smoking during pregnancy, the long-term consequences for the offspring remain elusive. Animal studies now suggest that maternal nicotine exposure during perinatal life leads to a wide range of adverse outcomes for the offspring including increased adiposity. The focus of this study was to investigate if nicotine exposure during pregnancy and lactation leads to alterations in hepatic triglyceride synthesis. Female Wistar rats were randomly assigned to receive daily subcutaneous injections of saline (vehicle) or nicotine bitartrate (1 mg/kg/day) for two weeks prior to mating until weaning. At postnatal day 180 (PND 180), nicotine exposed offspring exhibited significantly elevated levels of circulating and hepatic triglycerides in the male offspring. This was concomitant with increased expression of fatty acid synthase (FAS), the critical hepatic enzyme in de novo triglyceride synthesis. Given that FAS is regulated by the nuclear receptor Liver X receptor (LXRα), we measured LXRα expression in both control and nicotine-exposed offspring. Nicotine exposure during pregnancy and lactation led to an increase in hepatic LXRα protein expression and enriched binding to the putative LXRE element on the FAS promoter in PND 180 male offspring. This was also associated with significantly enhanced acetylation of histone H3 [K9,14] surrounding the FAS promoter, a hallmark of chromatin activation. Collectively, these findings suggest that nicotine exposure during pregnancy and lactation leads to an increase in circulating and hepatic triglycerides long-term via changes in the transcriptional and epigenetic regulation of the hepatic lipogenic pathway. - Highlights: • Our data reveals the links nicotine exposure in utero and long-term hypertriglyceridemia. • It is due to nicotine-induced augmented expression of hepatic FAS and LXRα activity. • Moreover, this involves nicotine-induced enhanced acetylation of histone H3 [K9,14]. • This provides a mechanism for developmental origins of health and disease (DOHaD)

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Prenatal nicotinic exposure suppresses fetal adrenal steroidogenesis via steroidogenic factor 1 (SF-1) deacetylation

This study aimed to investigate the suppressive effect of nicotine on fetal adrenal steroidogenesis and to explore the potential role of epigenetic modification of steroidogenic factor-1 (SF-1) transcriptional activity in this process. Nicotine was intragastrically administered to pregnant rats and NCI-H295A cells were treated with nicotine or trichostatin A (TSA). The pathomorphology of fetal adrenals, steroid hormone levels, the expression of SF-1 and its target genes, and histone deacetylase (HDAC) mRNA were analyzed. Histone modification and DNA methylation of the SF-1 promoter region were assessed using chromatin immunoprecipitation (ChIP) and bisulfite sequencing PCR. The interaction between SF1 and its target genes was observed. Prenatal nicotinic exposure decreased fetal body weight, increased the IUGR rate and caused detrimental changes in fetal adrenal. In addition, the levels of corticosterone, the expression of SF-1 and its target genes were decreased while HDAC2 expression was enhanced. Nicotine treatment decreased histone H3K9 and H3K14 acetylation levels while there was no effect on the methylation frequency on the SF-1 promoter region. Furthermore, in nicotine-treated NCI-H295A cells, lower levels of steroidogenic synthesis, lower expression of SF-1 and its target genes were observed while the expression of HDACs was enhanced. The interaction between SF1 and StAR decreased with nicotine treatment. Nicotine treatment decreased histone H3K9 and H3K14 acetylation levels, and addition of TSA reversed the inhibition of nicotine-mediated SF-1 and its partial target genes. Thus, nicotine-mediated reduction of SF-1 expression resulted in an inhibitory effect on the expression of its target genes and steroid production via histone deacetylation. - Highlights: • Prenatal nicotine-exposed suppresses fetal adrenal steroidogenesis. • Nicotine-supressed fetal adrenal steroidogenesis is related to SF-1 deacetylation. • Prenatal nicotinic exposure decreased fetal adrenal SF-1 acetylation. • Prenatal nicotine-exposed damages fetal adrenal mitochondrial structure.

60 APPLIED LIFE SCIENCES↗