Multiparametric Profiling of Circulating Immune Cells Identifies an Expansion of CD25 Switched Memory B Cells in Osteoarthritis.

Objective: Osteoarthritis (OA) is a chronic, debilitating disease with no available disease-modifying drugs. Biomarker identification in patients with OA has hitherto been limited to serum proteins and bulk epigenomic feature identification.

Methods: Peripheral blood mononuclear cells (PBMCs) from 21 healthy donors, 17 patients with OA, and 10 patients with degenerative meniscal tears (DMTs) were immunophenotyped at single-cell resolution by mass cytometry by time-of-flight using a 29-marker panel to identify OA-associated features in the circulating immune cells.

Paternal alcohol exposures program intergenerational hormetic effects on offspring fetoplacental growth.

Hormesis refers to graded adaptive responses to harmful environmental stimuli where low-level toxicant exposures stimulate tissue growth and responsiveness while, in contrast, higher-level exposures induce toxicity. Although the intergenerational inheritance of programmed hormetic growth responses is described in plants and insects, researchers have yet to observe this phenomenon in mammals. Using a physiologically relevant mouse model, we demonstrate that chronic preconception paternal alcohol exposures program nonlinear, dose-dependent changes in offspring fetoplacental growth.

Alcohol induced increases in sperm Histone H3 lysine 4 trimethylation correlate with increased placental CTCF occupancy and altered developmental programming.

Using a mouse model, studies by our group reveal that paternal preconception alcohol intake affects offspring fetal-placental growth, with long-lasting consequences on adult metabolism. Here, we tested the hypothesis that chronic preconception male alcohol exposure impacts histone enrichment in sperm and that these changes are associated with altered developmental programming in the placenta. Using chromatin immunoprecipitation, we find alcohol-induced increases in sperm histone H3 lysine 4 trimethylation (H3K4me3) that map to promoters and presumptive enhancer regions enriched in genes driving neurogenesis and craniofacial development.

Chromatin alterations during the epididymal maturation of mouse sperm refine the paternally inherited epigenome.

Background: Paternal lifestyle choices and male exposure history have a critical influence on the health and fitness of the next generation. Accordingly, defining the processes of germline programming is essential to resolving how the epigenetic memory of paternal experiences transmits to their offspring. Established dogma holds that all facets of chromatin organization and histone posttranslational modification are complete before sperm exits the testes.

Maternal background alters the penetrance of growth phenotypes and sex-specific placental adaptation of offspring sired by alcohol-exposed males.

Epigenetic mechanisms of paternal inheritance are an emerging area of interest in our efforts to understand fetal alcohol spectrum disorders. In rodent models examining maternal alcohol exposures, different maternal genetic backgrounds protect or sensitize offspring to alcohol-induced teratogenesis. However, whether maternal background can mitigate sperm-inherited alterations in developmental programming and modify the penetrance of growth defects induced by preconception paternal alcohol exposures remains unaddressed.

Programmed increases in LXRα induced by paternal alcohol use enhance offspring metabolic adaptation to high-fat diet induced obesity.

Objectives: Paternally inherited alterations in epigenetic programming are emerging as relevant factors in numerous disease states, including the growth and metabolic defects observed in fetal alcohol spectrum disorders. In rodents, chronic paternal alcohol use induces fetal growth restriction, as well as sex-specific alterations in insulin signaling and lipid homeostasis in the offspring. Based on previous studies, we hypothesized that the observed metabolic irregularities are the consequence of paternally inherited alterations liver x receptor (LXR) activity.

DNA methylation-independent growth restriction and altered developmental programming in a mouse model of preconception male alcohol exposure.

The preconception environment is a significant modifier of dysgenesis and the development of environmentally-induced disease. To date, fetal alcohol spectrum disorders (FASDs) have been exclusively associated with maternal exposures, yet emerging evidence suggests male-inherited alterations in the developmental program of sperm may be relevant to the growth-restriction phenotypes of this condition. Using a mouse model of voluntary consumption, we find chronic preconception male ethanol exposure associates with fetal growth restriction, decreased placental efficiency, abnormalities in cholesterol trafficking, sex-specific alterations in the genetic pathways regulating hepatic fibrosis, and disruptions in the regulation of imprinted genes.

Disconnect between alcohol-induced alterations in chromatin structure and gene transcription in a mouse embryonic stem cell model of exposure.

Alterations to chromatin structure induced by environmental insults have become an attractive explanation for the persistence of exposure effects into subsequent life stages. However, a growing body of work examining the epigenetic impact that alcohol and other drugs of abuse exert consistently notes a disconnection between induced changes in chromatin structure and patterns of gene transcription. Thus, an important question is whether perturbations in the 'histone code' induced by prenatal exposures to alcohol implicitly subvert gene expression, or whether the hierarchy of cellular signaling networks driving development is such that they retain control over the transcriptional program.

Mono-(2-ethylhexyl) phthalate induces apoptosis through miR-16 in human first trimester placental cell line HTR-8/SVneo.

Phthalates have been linked to adverse pregnancy complications. Mono-(2-ethylhexyl) phthalate, an active metabolite of di-(2-ethylhexyl) phthalate and an endocrine disruptor, has been shown to induce apoptosis in various cell types including placental cells. However, the mechanism of action of MEHP induced apoptosis is still unknown.

The plasticizer BBP selectively inhibits epigenetic regulator sirtuins.

The plasticizer benzyl butyl phthalate (BBP) is a well-known endocrine disruptor. Widespread human exposure to phthalates has raised substantial public concern due to its detrimental health effects. However, molecular mechanisms of the phthalates effect require elucidation.

Pyrroloquinoline quinone increases the expression and activity of Sirt1 and -3 genes in HepG2 cells.

Sirtuin (Sirt) 1 and Sirt 3 are nicotinamide adenine dinucleotide ((+))-dependent protein deacetylases that are important to a number of mitochondrial-related functions; thus, identification of sirtuin activators is important. Herein, we hypothesize that pyrroloquinoline quinone (PQQ) can act as a Sirt1/Sirt3 activator. In HepG2 cell cultures, PQQ increased the expression of Sirt1 and Sirt3 gene, protein, and activity levels (P < .