553 research outputs found
Maternal self-reported prenatal depressive symptoms predict infant NR3C1 1F and BDNF IV DNA methylation.
Prenatal maternal psychological distress increases risk for adverse infant outcomes.
However, the biological mechanisms underlying this association remain unclear.
Prenatal stress can impact fetal epigenetic regulation that could underlie changes in
infant stress responses. It has been suggested that maternal glucocorticoids may
mediate this epigenetic effect. We examined this hypothesis by determining the
impact of maternal cortisol and depressive symptoms during pregnancy on infant
NR3C1 and BDNF DNA methylation. Fifty-seven pregnant women were recruited
during the second or third trimester.
Participants self-reported depressive symptoms
and salivary cortisol samples were collected diurnally and in response to a stressor.
Buccal swabs for DNA extraction and DNA methylation analysis were collected from
each infant at two months of age, and mothers were assessed for postnatal depressive
symptoms. Prenatal depressive symptoms significantly predicted increased NR3C1 1F
DNA methylation in male infants ( 2.147 = س , P = 0.044). Prenatal depressive
symptoms also significantly predicted decreased BDNF IV DNA methylation in both
male and female infants ( -3.244 = س , P = 0.013). No measure of maternal cortisol
during pregnancy predicted infant NR3C1 1F or BDNF promoter IV DNA
methylation. Our findings highlight the susceptibility of males to changes in NR3C1
DNA methylation and present novel evidence for altered BDNF IV DNA methylation
in response to maternal depression during pregnancy. The lack of association between
maternal cortisol and infant DNA methylation suggests that effects of maternal
depression may not be mediated directly by glucocorticoids. Future studies should
consider other potential mediating mechanisms in the link between maternal mood
and infant outcome
Developing Effective Alzheimer's Disease Therapies: Clinical Experience and Future Directions
Alzheimer's disease (AD) clinical trials, focused on disease modifying drugs and conducted in patients with mild to moderate AD, as well as prodromal (early) AD, have failed to reach efficacy endpoints in improving cognitive function in most cases to date or have been terminated due to adverse events. Drugs that have reached clinical stage were reviewed using web resources (such as clinicaltrials.gov, alzforum.org, company press releases, and peer reviewed literature) to identify late stage (Phase II and Phase III) efficacy clinical trials and summarize reasons for their failure. For each drug, only the latest clinical trials and ongoing trials that aimed at improving cognitive function were included in the analysis. Here we highlight the potential reasons that have hindered clinical success, including clinical trial design and choice of outcome measures, heterogeneity of patient populations, difficulties in diagnosing and staging the disease, drug design, mechanism of action, and toxicity related to the long-term use. We review and suggest approaches for AD clinical trial design aimed at improving our ability to identify novel therapies for this devastating disease
Low-temperature water-gas shift reaction over Cu- and Ni-loaded cerium oxide catalysts
Sex and Estrous Cycle Effects on Anxiety- and Depression-Related Phenotypes in a Two-Hit Developmental Stress Model
Stress during sensitive developmental periods can adversely affect physical and psychological development and contribute to later-life mental disorders. In particular, adverse experiences during childhood dramatically increase the risk for the development of depression and anxiety disorders. Although women of reproductive age are twice as likely to develop anxiety and depression than men of the corresponding age, little is known about sex-specific factors that promote or protect against the development of psychopathology. To examine potential developmental mechanisms driving sex disparity in risk for anxiety and depression, we established a two-hit developmental stress model including maternal separation in early life followed by social isolation in adolescence. Our study shows complex interactions between early-life and adolescent stress, between stress and sex, and between stress and female estrogen status in shaping behavioral phenotypes of adult animals. In general, increased locomotor activity and body weight reduction were the only two phenotypes where two stressors showed synergistic activity. In terms of anxiety- and depression-related phenotypes, single exposure to early-life stress had the most significant impact and was female-specific. We show that early-life stress disrupts the protective role of estrogen in females, and promotes female vulnerability to anxiety- and depression-related phenotypes associated with the low-estrogenic state. We found plausible transcriptional and epigenetic alterations in psychiatric risk genes, Nr3c1 and Cacna1c, that likely contributed to the stress-induced behavioral effects. In addition, two general transcriptional regulators, Egr1 and Dnmt1, were found to be dysregulated in maternally-separated females and in animals exposed to both stressors, respectively, providing insights into possible transcriptional mechanisms that underlie behavioral phenotypes. Our findings provide a novel insight into developmental risk factors and biological mechanisms driving sex differences in depression and anxiety disorders, facilitating the search for more effective, sex-specific treatments for these disorders
Bisphenol A shapes children’s brain and behavior: towards an integrated neurotoxicity assessment including human data
The authors gratefully acknowledge editorial assistance provided by Richard
Davies. VM is under contract within the Human Biomonitoring for Europe
Project (European Union Commission H2020-EJP-HBM4EU). The authors acknowledge the funding received from the Biomedical Research Networking
Center-CIBER de Epidemiología y Salud Pública (CIBERESP), and the Instituto
de Salud Carlos III (ISCIII) (FIS-PI16/01820 and FIS-PI16/01812). The funders
had no role in the study design, data.Concerns about the effects of bisphenol A (BPA) on human brain and behavior are not novel; however, Grohs and
colleagues have contributed groundbreaking data on this topic in a recent issue of Environmental Health. For the first time,
associations were reported between prenatal BPA exposure and differences in children’s brain microstructure, which
appeared to mediate the association between this exposure and children’s behavioral symptoms. Findings in numerous
previous mother-child cohorts have pointed in a similar worrying direction, linking higher BPA exposure during pregnancy
to more behavioral problems throughout childhood as assessed by neuropsychological questionnaires. Notwithstanding, this
body of work has not been adequately considered in risk assessment. From a toxicological perspective, results are now
available from the CLARITY-BPA consortium, designed to reconcile academic and regulatory toxicology findings. In fact, the
brain has consistently emerged as one of the most sensitive organs disrupted by BPA, even at doses below those
considered safe by regulatory agencies such as the European Food Safety Authority (EFSA). In this Commentary, we
contextualize the results of Grohs et al. within the setting of previous epidemiologic and CLARITY-BPA data and express our
disquiet about the “all-or-nothing” criterion adopted to select human data in a recent EFSA report on the appraisal
methodology for their upcoming BPA risk assessment. We discuss the most relevant human studies, identify emerging
patterns, and highlight the need for adequate assessment and interpretation of the increasing epidemiologic literature in this
field in order to support decision-making. With the aim of avoiding a myopic or biased selection of a few studies in
traditional risk assessment procedures, we propose a future reevaluation of BPA focused on neurotoxicity and based on a
systematic and comprehensive integration of available mechanistic, animal, and human data. Taken together, the
experimental and epidemiologic evidence converge in the same direction: BPA is a probable developmental neurotoxicant
at low doses. Accordingly, the precautionary principle should be followed, progressively implementing stringent preventive
policies worldwide, including the banning of BPA in food contact materials and thermal receipts, with a focus on the
utilization of safer substitutes.European Union (EU): H2020-EJP-HBM4EUBiomedical Research Networking Center-CIBER de Epidemiologia y Salud Publica (CIBERESP)Instituto de Salud Carlos III
FIS-PI16/01820
FIS-PI16/0181
Epigenetic responses following maternal dietary exposure to physiologically relevant levels of bisphenol A
Animal studies have linked perinatal bisphenol A (BPA) exposure to altered DNA methylation, but little attention is given to analyzing multiple physiologically relevant doses. Utilizing the viable yellow agouti ( A vy ) mouse, we examine the effects of developmental exposure through maternal diet to 50 ng BPA/kg ( n = 14 litters), 50 μg BPA/kg ( n = 9 litters), or 50 mg BPA/kg ( n = 13 litters) on global and candidate gene methylation at postnatal day 22. Global methylation analysis reveals hypermethylation in tail tissue of a/a and A vy /a offspring across all dose groups compared with controls ( n = 11 litters; P < 0.02). Analysis of coat color phenotype replicates previous work showing that the distribution of 50 mg BPA/kg A vy /a offspring shifts toward yellow ( P = 0.006) by decreasing DNA methylation in the retrotransposon upstream of the Agouti gene ( P = 0.03). Maternal exposure to 50 μg or 50 ng BPA/kg, however, results in altered coat color distributions in comparison with control ( P = 0.04 and 0.02), but no DNA methylation effects at the Agouti gene are noted. DNA methylation at the CDK5 activator‐binding protein ( Cabp IAP ) metastable epiallele shows hypermethylation in the 50 μg BPA/kg offspring, compared with controls ( P = 0.02). Comparison of exposed mouse liver BPA levels to human fetal liver BPA levels indicates that the three experimental exposures are physiologically relevant. Thus, perinatal BPA exposure affects offspring phenotype and epigenetic regulation across multiple doses, indicating the need to evaluate dose effects in human clinical and population studies. Environ. Mol. Mutagen. 2012. © 2012 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91363/1/21692_ftp.pd
Continuous catalytic upgrading of ethanol to n-butanol and >C-4 products over Cu/CeO2 catalysts in supercritical CO2
n-Butanol (BuOH) often has superior properties as a bio-fuel compared to ethanol (EtOH). However finding sustainable sources of BuOH is proving difficult. In this paper, direct production of BuOH from EtOH is compared over custom-synthesized six Cu catalysts, supported on different solid acids. These catalysts were tested in a continuous flow supercritical CO2 (scCO2) reactor, and were found to catalyse the dehydrogenation, aldol condensation and hydrogenation steps of the so-called Guerbet reaction converting EtOH to BuOH. BuOH yields and selectivities were significantly different over the four catalysts. Cu on high surface area CeO2 showed the best activity for BuOH formation, with yields above 30% achieved with good selectivity. In addition high pressure CO2 is shown to have a positive effect on the reaction, possibly due to the redox cycle of Ce2O3 and CeO2
Epigenetic management of major psychosis
Epigenetic mechanisms are thought to play a major role in the pathogenesis of the major psychoses (schizophrenia and bipolar disorder), and they may be the link between the environment and the genome in the pathogenesis of these disorders. This paper discusses the role of epigenetics in the management of major psychosis: (1) the role of epigenetic drugs in treating these disorders. At present, there are three categories of epigenetic drugs that are being actively investigated for their ability to treat psychosis: drugs inhibiting histone deacetylation; drugs decreasing DNA methylation; and drugs targeting microRNAs; and (2) the role of epigenetic mechanisms in electroconvulsive therapy in these disorders
- …