Aim: Sex-based differences in response to adverse prenatal environments and infant outcomes have been observed, yet the underlying mechanisms for this are unclear. The placental epigenome may be a driver of these differences. Methods: Placental DNA methylation was assessed at more than 480,000 CpG sites from male and female infants enrolled in the extremely low gestational age newborns cohort (ELGAN) and validated in a separate US-based cohort. The impact of gestational age on placental DNA methylation was further examined using the New Hampshire Birth Cohort Study for a total of n = 467 placentas. Results: A total of n = 2745 CpG sites, representing n = 587 genes, were identified as differentially methylated (p < 1 × 10 -7 ). The majority (n = 582 or 99%) of these were conserved among the New Hampshire Birth Cohort. The identified genes encode proteins related to immune function, growth/transcription factor signaling and transport across cell membranes. Conclusion: These data highlight sex-dependent epigenetic patterning in the placenta and provide insight into differences in infant outcomes and responses to the perinatal environment.

Exposure to environmental contaminants during pregnancy has been linked to adverse outcomes at birth and later in life. The link between prenatal exposures and latent health outcomes suggests that these exposures may result in long-term epigenetic reprogramming. Toxic metals and endocrine disruptors are two major classes of contaminants that are ubiquitously present in the environment and represent threats to human health. In this review, we present evidence that prenatal exposures to these contaminants result in fetal epigenomic changes, including altered global DNA methylation, gene-specific CpG methylation and microRNA expression. Importantly, these changes may have functional cellular consequences, impacting health outcomes later in life. Therefore, these epigenetic changes represent a critical mechanism that warrants further study.

Background Exposures to toxic metals and deficiencies in essential metals disrupt placentation and may contribute to preeclampsia. However, effects of exposure to combinations of metals remain unknown. Objective We investigated the relationship between urinary trace metals, circulating angiogenic biomarkers, and preeclampsia using the LIFECODES birth cohort. Methods Urine samples collected during pregnancy were analyzed for 17 trace metals and plasma samples were analyzed for soluble fms-like tyrosine-1 (sFlt-1) and placental growth factor (PlGF). Cox proportional hazard models were used to estimate the hazard ratios (HR) of preeclampsia associated with urinary trace metals. Linear regression models were used to estimate the relationship between urinary trace metals and angiogenic biomarkers. Principal components analysis (PCA) was used to identify groups of metals and interactions between principal components (PCs) loaded by toxic and essential metals were examined. Results In single-contaminant models, several toxic and essential metals were associated with lower PlGF and higher sFlt-1/PlGF ratio. Detection of urinary chromium was associated with preeclampsia: HR (95% Confidence Interval [CI]) = 3.48 (1.02, 11.8) and an IQR-increase in urinary selenium was associated with reduced risk of preeclampsia (HR: 0.28, 95% CI: 0.08, 0.94). Using PCA, 3 PCs were identified, characterized by essential metals (PC1), toxic metals (PC2), and seafood-associated metals (PC3). PC1 and PC2 were associated with lower PlGF levels, but not preeclampsia risk in the overall cohort. Conclusions Trace urinary metals may be associated with adverse profiles of angiogenic biomarkers and preeclampsia. Electronic supplementary material The online version of this article (10.1186/s12940-019-0503-5) contains supplementary material, which is available to authorized users.

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Regulator of G protein signaling (RGS) proteins interact with activated G␣ subunits via their RGS domains and accelerate the hydrolysis of GTP. Although the R4 subfamily of RGS proteins generally accepts both G␣ i/o and G␣ q/11 subunits as substrates, the R7 and R12 subfamilies select against G␣ q/11 . In contrast, only one RGS protein, RGS2, is known to be selective for G␣ q/11 . The molecular basis for this selectivity is not clear. Previously, the crystal structure of RGS2 in complex with G␣ q revealed a non-canonical interaction that could be due to interfacial differences imposed by RGS2, the G␣ subunit, or both. To resolve this ambiguity, the 2.6 Å crystal structure of RGS8, an R4 subfamily member, was determined in complex with G␣ q . RGS8 adopts the same pose on G␣ q as it does when bound to G␣ i3 , indicating that the non-canonical interaction of RGS2 with G␣ q is due to unique features of RGS2. Based on the RGS8-G␣ q structure, residues in RGS8 that contact a unique ␣-helical domain loop of G␣ q were converted to those typically found in R12 subfamily members, and the reverse substitutions were introduced into RGS10, an R12 subfamily member. Although these substitutions perturbed their ability to stimulate GTP hydrolysis, they did not reverse selectivity. Instead, selectivity for G␣ q seems more likely determined by whether strong contacts can be maintained between ␣6 of the RGS domain and Switch III of G␣ q , regions of high sequence and conformational diversity in both protein families.Many transmembrane signaling events are transduced inside the cell by heterotrimeric G proteins, which are activated by cell surface G protein-coupled receptors. G protein-coupled receptors stimulate the exchange of bound GDP for GTP on the G␣ subunit, which then separates from the G␤␥ subunits and interacts with downstream effectors (1). After hydrolyzing GTP to GDP, the G␣ subunit is deactivated and is rapidly sequestered by G␤␥. In biological processes, such as the visual response, deactivation of G␣ has been observed at much faster rates than those measured for isolated G␣ subunits in vitro (2, 3). This discrepancy helped lead to the discovery of a family of GTPaseactivating proteins (GAPs), 2 now known as regulator of G protein signaling (RGS) proteins (4 -6). RGS proteins contain a conserved helical domain called the RGS domain that directly binds to the three switch regions (SwI-III) of the G␣ subunit and stabilizes them in a transition state conformation (7).RGS domains are divided into four subfamilies based on sequence homology and substrate preference: RZ, R4, R7, and R12 (8). All utilize G␣ i/o subunits as substrates, although some RZ members seem selective for G␣ z subunits (9). A recent study using surface plasmon resonance indicated that the RGS domains that belong to the R7 and R12 subfamilies bind weakly or not at all to G␣ q , whereas the RZ and R4 subfamilies tend to interact with both G␣ i/o and G␣ q/11 (10). The exception is RGS2, an R4 subfamily member that is uniquely selective for G␣ q/11 (11). ...

Background: Arsenic, cadmium, lead, and mercury are ubiquitous toxicants that may be especially harmful to unborn children. We therefore sought to identify temporal trends and predictors of toxic metal biomarkers among US women of reproductive age, including those who were pregnant and/or breastfeeding. Methods: Interviews and examinations were performed among a representative sample of women, aged 20 to 44 years, as part of the 2003-2014 National Health and Nutrition Examination Surveys. A range of sociodemographic, lifestyle, and dietary factors were evaluated as predictors of urinary inorganic arsenic, urinary cadmium, blood mercury, and blood lead concentrations. Results: Levels of all four toxic metal biomarkers declined during the study period. Older age, racial/ethnic minorities, and a birthplace outside of the US were independently associated with higher toxic metal concentrations. Associations were similar for women who were pregnant or breastfeeding and those who were not. Conclusion: US women of reproductive age were exposed to lower levels of toxic metals in 2013-2014 compared to 2003-2004. However, because the long-term health effects of early life exposures are unclear, public health efforts to address toxic metals should pay particular attention to older, non-white, and foreign-born women if they are pregnant or planning to become pregnant.

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Arsenic (As) is a toxic metalloid. Inorganic arsenic (iAs) is a form of As commonly found in drinking water and in some foods. Overwhelming evidence suggest that people chronically exposed to iAs are at risk of developing cancer, or cardiovascular, neurological and metabolic diseases. Although the mechanisms underlying iAs-associated illness remain poorly characterized, a growing body of literature raises the possibility that microRNAs (miRNAs), post-transcriptional gene suppressors, may serve as mediators and/or early indicators of the pathologies associated with iAs exposure.