Differential DNA Methylation in Umbilical Cord Blood of Infants Exposed to Low Levels of Arsenic in Utero

Background: There is increasing epidemiologic evidence that arsenic exposure in utero, even at low levels found throughout much of the world, is associated with adverse reproductive outcomes and may contribute to long-term health effects. Animal models, in vitro studies, and human cancer data suggest that arsenic may induce epigenetic alterations, specifically by altering patterns of DNA methylation. Objectives: In this study we aimed to identify differences in DNA methylation in cord blood samples of infants with in utero, low-level arsenic exposure. Methods: DNA methylation of cord-blood derived DNA from 134 infants involved in a prospective birth cohort in New Hampshire was profiled using the Illumina Infinium Methylation450K array. In utero arsenic exposure was estimated using maternal urine samples collected at 24–28 weeks gestation. We used a novel cell mixture deconvolution methodology for examining the association between inferred white blood cell mixtures in infant cord blood and in utero arsenic exposure; we also examined the association between methylation at individual CpG loci and arsenic exposure levels. Results: We found an association between urinary inorganic arsenic concentration and the estimated proportion of CD8+ T lymphocytes (1.18; 95% CI: 0.12, 2.23). Among the top 100 CpG loci with the lowest p-values based on their association with urinary arsenic levels, there was a statistically significant enrichment of these loci in CpG islands (p = 0.009). Of those in CpG islands (n = 44), most (75%) exhibited higher methylation levels in the highest exposed group compared with the lowest exposed group. Also, several CpG loci exhibited a linear dose-dependent relationship between methylation and arsenic exposure. Conclusions: Our findings suggest that in utero exposure to low levels of arsenic may affect the epigenome. Long-term follow-up is planned to determine whether the observed changes are associated with health outcomes

Exposure and fetal growth-associated miRNA alterations in the human placenta

Researchers have begun to examine epigenetic alterations in the placenta, making key advances in understanding the epigenetic regulatory mechanisms of the placenta that define underlying processes of human development and disease. Examining changes in microRNA (miRNA) expression associated with environmental exposures and fetal growth is providing critical insights into the biology of development, response to in utero exposure, and future disease risk assessment. This review aims to highlight previous studies describing changes in miRNA expression in the human placenta associated with in utero exposure and fetal growth and seeks to assess the future directions in this exciting field of research

miR-16 and miR-21 Expression in the Placenta Is Associated with Fetal Growth

BACKGROUND: Novel research has suggested that altered miRNA expression in the placenta is associated with adverse pregnancy outcomes and with potentially harmful xenobiotic exposures. We hypothesized that aberrant expression of miRNA in the placenta is associated with fetal growth, a measurable phenotype resulting from a number of intrauterine factors, and one which is significantly predictive of later life outcomes. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed 107 primary, term, human placentas for expression of 6 miRNA reported to be expressed in the placenta and to regulate cell growth and development pathways: miR-16, miR-21, miR-93, miR-135b, miR-146a, and miR-182. The expression of miR-16 and miR-21 was markedly reduced in infants with the lowest birthweights (p<0.05). Logistic regression models suggested that low expression of miR-16 in the placenta predicts an over 4-fold increased odds of small for gestational age (SGA) status (p = 0.009, 95% CI = 1.42, 12.05). Moreover, having both low miR-16 and low miR-21 expression in the placenta predicts a greater increase in odds for SGA than having just low miR-16 or miR-21 expression (p<0.02), suggesting an additive effect of both of these miRNA. CONCLUSIONS/SIGNIFICANCE: Our study is one of the first to investigate placental miRNA expression profiles associated with birthweight and SGA status. Future research on miRNA whose expression is associated with in utero exposures and markers of fetal growth is essential for better understanding the epigenetic mechanisms underlying the developmental origins of health and disease

Recommendations for accelerating open preprint peer review to improve the culture of science

Peer review is an important part of the scientific process, but traditional peer review at journals is coming under increased scrutiny for its inefficiency and lack of transparency. As preprints become more widely used and accepted, they raise the possibility of rethinking the peer-review process. Preprints are enabling new forms of peer review that have the potential to be more thorough, inclusive, and collegial than traditional journal peer review, and to thus fundamentally shift the culture of peer review toward constructive collaboration. In this Consensus View, we make a call to action to stakeholders in the community to accelerate the growing momentum of preprint sharing and provide recommendations to empower researchers to provide open and constructive peer review for preprints

Recommendations for accelerating open preprint peer review to improve the culture of science

Peer review is an important part of the scientific process, but traditional peer review at journals is coming under increased scrutiny for its inefficiency and lack of transparency. As preprints become more widely used and accepted, they raise the possibility of rethinking the peer-review process. Preprints are enabling new forms of peer review that have the potential to be more thorough, inclusive, and collegial than traditional journal peer review, and to thus fundamentally shift the culture of peer review toward constructive collaboration. In this Consensus View, we make a call to action to stakeholders in the community to accelerate the growing momentum of preprint sharing and provide recommendations to empower researchers to provide open and constructive peer review for preprints

Downstream retraction of preprinted research in the life and medical sciences

Retractions have been on the rise in the life and clinical sciences in the last decade, likely due to both broader accessibility of published scientific research and increased vigilance on the part of publishers. In this same period, there has been a greater than ten-fold increase in the posting of preprints by researchers in these fields. While this development has significantly accelerated the rate of research dissemination and has benefited early-career researchers eager to show productivity, it has also introduced challenges with respect to provenance tracking, version linking, and, ultimately, back-propagation of events such as corrigenda, expressions of concern, and retractions that occur on the journal-published version. The aim of this study was to understand the extent of this problem among preprint servers that routinely link their preprints to the corollary versions published in journals. To present a snapshot of the current state of downstream retractions of articles preprinted in three large preprint servers (Research Square, bioRxiv, and medRxiv), the DOIs of the journal-published versions linked to preprints were matched to entries in the Retraction Watch database. A total of 30 retractions were identified, representing only 0.01% of all content posted on these servers. Of these, 11 retractions were clearly noted by the preprint servers; however, the existence of a preprint was only acknowledged by the retracting journal in one case. The time from publication to retraction averaged 278 days, notably lower than the average for articles overall (839 days). In 70% of cases, retractions downstream of preprints were due – at least in part – to ethical or procedural misconduct. In 63% of cases, the nature of the retraction suggested that the conclusions were no longer reliable. Over time, the lack of propagation of critical information across the publication life cycle will pose a threat to the scholarly record and to scientific integrity. It is incumbent on preprint servers, publishers, and the systems that connect them to address these issues before their scale becomes untenable

Downstream retraction of preprinted research in the life and medical sciences

Retractions have been on the rise in the life and clinical sciences in the last decade, likely due to both broader accessibility of published scientific research and increased vigilance on the part of publishers. In this same period, there has been a greater than ten-fold increase in the posting of preprints by researchers in these fields. While this development has significantly accelerated the rate of research dissemination and has benefited early-career researchers eager to show productivity, it has also introduced challenges with respect to provenance tracking, version linking, and, ultimately, back-propagation of events such as corrigenda, expressions of concern, and retractions that occur on the journal-published version. The aim of this study was to understand the extent of this problem among preprint servers that routinely link their preprints to the corollary versions published in journals. To present a snapshot of the current state of downstream retractions of articles preprinted in three large preprint servers (Research Square, bioRxiv, and medRxiv), the DOIs of the journal-published versions linked to preprints were matched to entries in the Retraction Watch database. A total of 30 retractions were identified, representing only 0.01% of all content posted on these servers. Of these, 11 retractions were clearly noted by the preprint servers; however, the existence of a preprint was only acknowledged by the retracting journal in one case. The time from publication to retraction averaged 278 days, notably lower than the average for articles overall (839 days). In 70% of cases, retractions downstream of preprints were due–at least in part–to ethical or procedural misconduct. In 63% of cases, the nature of the retraction suggested that the conclusions were no longer reliable. Over time, the lack of propagation of critical information across the publication life cycle will pose a threat to the scholarly record and to scientific integrity. It is incumbent on preprint servers, publishers, and the systems that connect them to address these issues before their scale becomes untenable.</jats:p

Downstream retraction of preprinted research in the life and medical sciences

Retractions have been on the rise in the life and clinical sciences in the last decade, likely due to both broader accessibility of published scientific research and increased vigilance on the part of publishers. In this same period, there has been a greater than ten-fold increase in the posting of preprints by researchers in these fields. While this development has significantly accelerated the rate of research dissemination and has benefited early-career researchers eager to show productivity, it has also introduced challenges with respect to provenance tracking, version linking, and, ultimately, back-propagation of events such as corrigenda, expressions of concern, and retractions that occur on the journal-published version. The aim of this study was to understand the extent of this problem among preprint servers that routinely link their preprints to the corollary versions published in journals. To present a snapshot of the current state of downstream retractions of articles preprinted in three large preprint servers (Research Square, bioRxiv, and medRxiv), the DOIs of the journal-published versions linked to preprints were matched to entries in the Retraction Watch database. A total of 30 retractions were identified, representing only 0.01% of all content posted on these servers. Of these, 11 retractions were clearly noted by the preprint servers; however, the existence of a preprint was only acknowledged by the retracting journal in one case. The time from publication to retraction averaged 278 days, notably lower than the average for articles overall (839 days). In 70% of cases, retractions downstream of preprints were due – at least in part – to ethical or procedural misconduct. In 63% of cases, the nature of the retraction suggested that the conclusions were no longer reliable. Over time, the lack of propagation of critical information across the publication life cycle will pose a threat to the scholarly record and to scientific integrity. It is incumbent on preprint servers, publishers, and the systems that connect them to address these issues before their scale becomes untenable.</p