Explore the vast range of titles available.

The exposome encompasses all life-course environmental exposures from the prenatal period onward that influence health. MicroRNAs (miRNAs) are interesting entities within this concept as markers and causation of disease. MicroRNAs are short oligonucleotide sequences that can interact with several mRNA targets. We reviewed the current state of the field on the potential of using miRNAs as biomarkers for environmental exposure. We investigated miRNA signatures in response to all types of environmental exposure to which a human can be exposed, including cigarette smoke, air pollution, nanoparticles, and diverse chemicals; and we examined the health conditions for which the identified miRNAs have been reported (i.e., cardiovascular disease, cancer, and diabetes). We searched the PubMed and ScienceDirect databases to identify relevant studies. For all exposures incorporated in this review, 27 miRNAs were differentially expressed in at least two independent studies. miRNAs that had expression alterations associated with smoking observed in multiple studies are miR-21, miR-34b, miR-125b, miR-146a, miR-223, and miR-340; and those miRNAs that were observed in multiple air pollution studies are miR-9, miR-10b, miR-21, miR-128, miR-143, miR-155, miR-222, miR-223, and miR-338. We found little overlap among in vitro, in vivo, and human studies between miRNAs and exposure. Here, we report on disease associations for those miRNAs identified in multiple studies on exposure. miRNA changes may be sensitive indicators of the effects of acute and chronic environmental exposure. Therefore, miRNAs are valuable novel biomarkers for exposure. Further studies should elucidate the role of the mediation effect of miRNA between exposures and effect through all stages of life to provide a more accurate assessment of the consequences of miRNA changes.

Background The micronutrient iodine is essential for a healthy intrauterine environment and is required for optimal fetal growth and neurodevelopment. Evidence linking urinary iodine concentrations, which mainly reflects short-term iodine intake, to gestational diabetes mellitus (GDM) is inconclusive. Although the placental concentrations would better reflect the long-term gestational iodine status, no studies to date have investigated the association between the placental iodine load and the risk at GDM. Moreover, evidence is lacking whether placental iodine could play a role in biomarkers of insulin resistance and β-cell activity. Methods We assessed the incidence of GDM between weeks 24 and 28 of gestation for 471 mother-neonate pairs from the ENVIR ON AGE birth cohort. In placentas, we determined the iodine concentrations. In maternal and cord blood, we measured the insulin concentrations, the Homeostasis Model Assessment (HOMA) for insulin resistance (IR) index, and β-cell activity. Logistic regression was used to estimate the odds ratios (OR) of GDM, and the population attributable factor (PAF) was calculated. Generalized linear models estimated the changes in insulin, HOMA-IR, and β-cell activity for a 5 μg/kg increase in placental iodine. Results Higher placental iodine concentrations decreased the risk at GDM (OR = 0.82; 95%CI 0.72 to 0.93; p  = 0.003). According to the PAF, 54.2% (95%CI 11.4 to 82.3%; p  = 0.0006) of the GDM cases could be prevented if the mothers of the lowest tertile of placental iodine would have placental iodine levels as those belonging to the highest tertile. In cord blood, the plasma insulin concentration was inversely associated with the placental iodine load ( β = − 4.8%; 95%CI − 8.9 to − 0.6%; p  = 0.026). Conclusions Higher concentrations of placental iodine are linked with a lower incidence of GDM. Moreover, a lower placental iodine load is associated with an altered plasma insulin concentration, HOMA-IR index, and β-cell activity. These findings postulate that a mild-to-moderate iodine deficiency could be linked with subclinical and early-onset alterations in the normal insulin homeostasis in healthy pregnant women. Nevertheless, the functional link between gestational iodine status and GDM warrants further research.

Background Parabens are a group of esters of para-hydroxybenzoic acid utilized as antimicrobial preservatives in many personal care products. Epidemiological studies regarding the adverse effects of parabens on fetuses are limited. The aim of this study was to determine the association between placental paraben exposure and birth outcomes. We assessed paraben concentrations in placental tissue, which potentially gives a better understanding of fetal exposure than the maternal urinary concentrations which are the current golden standard. Methods Placental tissue was collected immediately after birth from 142 mother-child pairs from the ENVIR ON AGE birth cohort. The placental concentrations of four parabens (methyl (MeP), ethyl (EtP), propyl (PrP), and butyl (BuP)) were determined by ultra-performance liquid chromatography coupled with tandem mass-spectrometry. Generalized linear regression models were used to determine the association between paraben exposure levels and birth outcomes. Results The geometric means of placental MeP, EtP, PrP, and BuP were 1.84, 2.16, 1.68 and 0.05 ng/g tissue, respectively. The sum of parabens (∑ parabens, including MeP, EtP and PrP) was negatively associated with birth weight in newborn girls (− 166 g, 95% CI: − 322, − 8.6, p  = 0.04) after adjustment for a priori selected covariates. The sum of parabens was negatively associated with head circumference (− 0.6 cm, 95% CI: − 1.1, − 0.2, p  = 0.008) and borderline associated with birth length (− 0.6 cm, 95% CI:-1.3, 0.1, p  = 0.08). In newborn girls the placental concentration of EtP was negatively associated with head circumference (− 0.6 cm, 95% CI:-1.1, − 0.1, p  = 0.01) and borderline significantly associated with birth weight and birth length. Lastly, placental EtP and ∑parabens were negatively associated with placental weight in newborn girls but not in newborn boys (− 45.3 g, 95% CI:-86.2, − 4.4, p  = 0.03). Conclusion The negative association between maternal paraben exposure and birth outcomes warrants further research and follow-up over time to determine long term effects of gestational exposure to parabens.

Background Iodine is an essential trace element for the production of thyroid hormones, and plays a key role during the gestational period for optimal foetal growth and (neuro-)development. To this day, iodine deficiency remains a global burden. Previous studies indicate that the placenta can store iodine in a concentration-dependent manner and serve as a long-term storage supply, but studies on the determinants of long-term placental iodine load are limited. Methods The placental iodine concentrations were determined for 462 mother-neonate pairs from the ENVIRONAGE birth cohort (Limburg, Belgium). Sociodemographic and clinical variables were obtained from questionnaires and medical files. Determinants of placental iodine concentration were identified using stepwise multiple regression procedures ( p value < 0.15). The biological significance of our findings was investigated by measuring the plasma thyroid hormones in maternal and cord blood of 378 participants. Results A higher pre-pregnancy BMI, higher gestational weight gain, and alcohol consumption during pregnancy were linked with lower placental iodine storage. Multi-vitamin supplementation during pregnancy and longer gestation were associated with higher levels of placental iodine. Children born during the winter period had on average higher placental iodine levels. Besides, we found a significant positive time trend for placental iodine load over the study period 2013 to 2017. Lastly, we observed positive associations of both the maternal and cord plasma thyroxine concentrations with placental iodine load, emphasizing their biological link. Conclusions This study identified some determinants likely presenting a risk of reduced iodine storage during the gestational period of life. Future studies should elucidate the effects of lower placental iodine load on neonatal health, and health later in life.

Background In the early-life environment, proper development of the placenta is essential for both fetal and maternal health. Telomere length at birth has been related to life expectancy. MicroRNAs (miRNAs) as potential epigenetic determinants of telomere length at birth have not been identified. In this study, we investigate whether placental miRNA expression is associated with placental telomere length at birth. Methods We measured the expression of seven candidate miRNAs (miR-16-5p, -20a-5p, -21-5p, -34a-5p, 146a-5p, -210-3p and -222-3p) in placental tissue at birth in 203 mother-newborn (51.7% girls) pairs from the ENVIR ON AGE birth cohort. We selected miRNAs known to be involved in crucial cellular processes such as inflammation, oxidative stress, cellular senescence related to aging. Placental miRNA expression and relative average placental telomere length were measured using RT-qPCR. Results Both before and after adjustment for potential covariates including newborn’s ethnicity, gestational age, paternal age, maternal smoking status, maternal educational status, parity, date of delivery and outdoor temperature during the 3rd trimester of pregnancy, placental miR-34a, miR-146a, miR-210 and miR-222 expression were significantly ( p  ≤  0.03 ) and positively associated with placental relative telomere length in newborn girls. In newborn boys, only higher expression of placental miR-21 was weakly ( p  =  0.08 ) associated with shorter placental telomere length. Significant miRNAs explain around 6–8% of the telomere length variance at birth. Conclusions Placental miR-21, miR-34a, miR-146a, miR-210 and miR-222 exhibit sex-specific associations with telomere length in placenta. Our results indicate miRNA expression in placental tissue could be an important determinant in the process of aging starting from early life onwards.

Background HIF1α, miR-210 and its downstream targets ISCU, COX-10, RAD52 and PTEN are all part of the placental hypoxia-responsive network. Tight regulation of this network is required to prevent development of maternal–fetal complications such as fetal growth restriction. HIF1α expression is increased in preeclamptic placentae, but little is known about its association with birth weight in normal pregnancies. Methods We measured placental levels of HIF1α , miR-20a, miR-210, ISCU , COX - 10 , RAD52 and PTEN in 206 mother–newborn pairs of the ENVIR ON AGE birth cohort. Results Placental HIF1α gene expression was inversely associated with the ponderal index (PI): for a doubling in placental HIF1α expression, PI decreased by 6.7% (95% confidence interval [CI] 1.3 to 12.0%, p = 0.01). Placental RAD52 expression also displayed an inverse association with PI, a doubling in gene expression was associated with a 6.2% (CI 0.2 to 12.1% p = 0.04) decrease in PI. As for birth weight, we observed a significant association with placental miR-20a expression only in boys, where a doubling in miR-20a expression is associated with a 54.2 g (CI 0.6 to 108 g, p = 0.05) increase in birth weight. Conclusions The decrease in fetal growth associated with expression of hypoxia-network members HIF1a, RAD52 and miR-20a indicates that this network is important in potential intrauterine insults.

Bone Morphogenetic Proteins (BMPs) are morphogens that play a major role in regulating development and homeostasis. Although BMPs are used for the treatment of bone and kidney disorders, their clinical use is limited due to the supra-physiological doses required for therapeutic efficacy causing severe side effects. Because recombinant BMPs are expensive to produce, small molecule activators of BMP signaling would be a cost-effective alternative with the added benefit of being potentially more easily deliverable. Here, we report our efforts to identify small molecule activators of BMP signaling. We have developed a cell-based assay to monitor BMP signaling by stably transfecting a BMP-responsive human cervical carcinoma cell line (C33A) with a reporter construct in which the expression of luciferase is driven by a multimerized BMP-responsive element from the Id1 promoter. A BMP-responsive clone C33A-2D2 was used to screen a bioactive library containing ∼5,600 small molecules. We identified four small molecules of the family of flavonoids all of which induced luciferase activity in a dose-dependent manner and ventralized zebrafish embryos. Two of the identified compounds induced Smad1, 5 phosphorylation (P-Smad), Id1 and Id2 expression in a dose-dependent manner demonstrating that our assays identified small molecule activators of BMP signaling.

There is increasing evidence that the predisposition for development of chronic diseases arises at the earliest times of life. In this context, maternal pre-pregnancy weight might modify fetal metabolism and the child’s predisposition to develop disease later in life. The aim of this study is to investigate the association between maternal pre-pregnancy body mass index (BMI) and miRNA alterations in placental tissue at birth. In 211 mother-newborn pairs from the ENVIR ON AGE birth cohort, we assessed placental expression of seven miRNAs important in crucial cellular processes implicated in adipogenesis and/or obesity. Multiple linear regression models were used to address the associations between pre-pregnancy BMI and placental candidate miRNA expression. Maternal pre-pregnancy BMI averaged (±SD) 23.9 (±4.1) kg/m 2 . In newborn girls (not in boys) placental miR-20a, miR-34a and miR-222 expression was lower with higher maternal pre-pregnancy BMI. In addition, the association between maternal pre-pregnancy BMI and placental expression of these miRNAs in girls was modified by gestational weight gain. The lower expression of these miRNAs in placenta in association with pre-pregnancy BMI, was only evident in mothers with low weight gain (<14 kg). The placental expression of miR-20a, miR-34a, miR-146a, miR-210 and miR-222 may provide a sex-specific basis for epigenetic effects of pre-pregnancy BMI.

An imbalance between energy uptake and energy expenditure is the most important reason for increasing trends in obesity starting from early in life. Extracellular miRNAs are expressed in all bodily fluids and their expression is influenced by a broad range of stimuli. We examined whether screen time, physical activity and BMI are associated with children’s salivary extracellular miR-222 and miR-146a expression. In 80 children the extracellular fraction of saliva was obtained by means of differential centrifugation and ultracentrifugation. Expression levels of miR-222 and miR-146a were profiled by qPCR. We studied the association between children’s salivary extracellular miRNA expression and screen time, physical activity and BMI using mixed models, while accounting for potential confounders. We found that higher screen time was positively associated with salivary extracellular miR-222 and miR-146a levels. On average, one hour more screen time use per week was associated with a 3.44% higher miR-222 (95% CI: 1.34 to 5.58; p = 0.002) and 1.84% higher miR-146a (95% CI: −0.04 to 3.75; p = 0.055) level in saliva. BMI and physical activity of the child were not significantly associated with either miR-222 or miR-146a. A sedentary behaviour, represented by screen time use in children, is associated with discernible changes in salivary expression of miR-146a and or miR-222. These miRNA targets may emerge attractive candidates to explore the role of these exposures in developmental processes of children’s health.

Background Due to their lack of repair capacity mitochondria are critical targets for environmental toxicants. We studied genes and pathways reflecting mitochondrial responses to short- and medium-term PM 10 exposure. Methods Whole genome gene expression was measured in peripheral blood of 98 adults (49% women). We performed linear regression analyses stratified by sex and adjusted for individual and temporal characteristics to investigate alterations in gene expression induced by short-term (week before blood sampling) and medium-term (month before blood sampling) PM 10 exposure. Overrepresentation analyses (ConsensusPathDB) were performed to identify enriched mitochondrial associated pathways and gene ontology sets. Thirteen Human MitoCarta genes were measured by means of quantitative real-time polymerase chain reaction (qPCR) along with mitochondrial DNA (mtDNA) content in an independent validation cohort ( n  = 169, 55.6% women). Results Overrepresentation analyses revealed significant pathways ( p -value <0.05) related to mitochondrial genome maintenance and apoptosis for short-term exposure and to the electron transport chain (ETC) for medium-term exposure in women. For men, medium-term PM 10 exposure was associated with the Tri Carbonic Acid cycle. In an independent study population, we validated several ETC genes, including UQCRH and COX7C ( q -value <0.05), and some genes crucial for the maintenance of the mitochondrial genome, including LONP1 ( q -value: 0.07) and POLG ( q -value: 0.04) in women. Conclusions In this exploratory study, we identified mitochondrial genes and pathways associated with particulate air pollution indicating upregulation of energy producing pathways as a potential mechanism to compensate for PM-induced mitochondrial damage.