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Background: Early childhood caries (ECC)-dental caries (cavities) occurring in primary teeth up to age 6 years-is a prevalent childhood oral disease with a microbial etiology. Streptococcus mutans was previously considered a primary cause, but recent research promotes the ecologic hypothesis, in which a dysbiosis in the oral microbial community leads to caries. In this incident, density sampled case-control study of 189 children followed from 2 months to 5 years, we use the salivary bacteriome to (1) prospectively test the ecological hypothesis of ECC in salivary bacteriome communities and (2) identify co-occurring salivary bacterial communities predicting future ECC., Results: Supervised classification of future ECC case status using salivary samples from age 12 months using bacteriome-wide data (AUC-ROC 0.78 95% CI (0.71-0.85)) predicts future ECC status before S. mutans can be detected. Dirichlet multinomial community state typing and co-occurrence network analysis identified similar robust and replicable groups of co-occurring taxa. Mean relative abundance of a Haemophilus parainfluenzae/Neisseria/Fusobacterium periodonticum group was lower in future ECC cases (0.14) than controls (0.23, P value < 0.001) in pre-incident visits, positively correlated with saliva pH (Pearson rho = 0.33, P value < 0.001) and reduced in individuals who had acquired S. mutans by the next study visit (0.13) versus those who did not (0.20, P value < 0.01). In a subset of whole genome shotgun sequenced samples (n = 30), case plaque had higher abundances of antibiotic production and resistance gene orthologs, including a major facilitator superfamily multidrug resistance transporter (MFS DHA2 family P BH value = 1.9 × 10 -28 ), lantibiotic transport system permease protein (P BH value = 6.0 × 10 -6 ) and bacitracin synthase I (P BH value = 5.6 × 10 -6 ). The oxidative phosphorylation KEGG pathway was enriched in case plaque (P BH value = 1.2 × 10 -8 ), while the ABC transporter pathway was depleted (P BH value = 3.6 × 10 -3 )., Conclusions: Early-life bacterial interactions predisposed children to ECC, supporting a time-dependent interpretation of the ecological hypothesis. Bacterial communities which assemble before 12 months of age can promote or inhibit an ecological succession to S. mutans dominance and cariogenesis. Intragenera competitions and intergenera cooperation between oral taxa may shape the emergence of these communities, providing points for preventive interventions. Video Abstract., (© 2022. The Author(s).)

Purpose of the Review: Exposure to essential and non-essential metals is widespread. Metals exposure is linked to epigenetic, particularly DNA methylation, differences. The strength of evidence with respect to the metal exposure type, timing, and level, as well as the DNA methylation association magnitude, and reproducibility are not clear. Focusing on the most recent 3 years, we reviewed the human epidemiologic evidence (n = 26 studies) and the toxicologic animal model evidence (n = 18 studies) for associations between metals exposure and DNA methylation., Recent Findings: In humans, the greatest number of studies focused on lead exposure, followed by studies examining cadmium and arsenic. Approximately half of studies considered metals exposure during the in utero period and measured DNA methylation with the genome-wide Illumina arrays in newborn blood or placenta. Few studies performed formal replication testing or meta-analyses. Toxicology studies of metals and epigenetics had diversity in model systems (mice, rats, drosophila, tilapia, and zebrafish were represented), high heterogeneity of tissues used for DNA methylation measure (liver, testis, ovary, heart, blood, brain, muscle, lung, kidney, whole embryo), and a variety of technologies used for DNA methylation assessment (global, gene specific, genome-wide). The most common metals tested in toxicologic studies were lead and cadmium. Together, the recent studies reviewed provide the strongest evidence for DNA methylation signatures with prenatal metals exposures. There is also mounting epidemiologic evidence supporting lead, arsenic, and cadmium exposures with DNA methylation signatures in adults. The field of metals and DNA methylation is strengthened by the inclusion of both epidemiology and toxicology approaches, and further advancements can be made by coordinating efforts or integrating analyses across studies. Future advances in understanding the molecular basis of sequence specific epigenetic responses to metals exposures, methods for handling exposure mixtures in a genome-wide analytic framework, and pipelines to facilitate collaborative testing will continue to advance the field., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

We examined maternal prenatal vitamin use or supplemental folic acid intake during month one of pregnancy for association with autism spectrum disorder (ASD) in the Early Autism Risk Longitudinal Investigation, an enriched-risk pregnancy cohort. Total folic acid intake was calculated from monthly prenatal vitamins, multivitamins, and other supplement reports. Clinical assessments through age 3 years classified children as ASD (n = 38) or non-ASD (n = 153). In pregnancy month one, prenatal vitamin use (59.7%) was not significantly associated with odds of ASD (OR = 0.70, 95%CI 0.32, 1.53). Sample size was limited and residual confounding was possible. Given the estimated effect sizes in this and previous work, prenatal vitamin intake during early pregnancy could be a clinically useful preventative measure for ASD., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder with genetic and environmental contributors to etiology. Many metals have the potential to be neurotoxic and their exposures are widespread. The field of metals exposure and ASD research is emerging, and in this review article we assess the current state of the literature, with emphasis on the previous two years. Epidemiology studies are discussed with respect to exposure timing, exposure matrix, and outcome assessment. Toxicology studies are described for exposure dosing and timing, as well as behavioral and molecular outcomes. Further epidemiological and toxicological investigations can identify the timing and importance of metals as ASD risk factors and uncover biological mechanisms for risk mitigation and therapeutic strategies., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Conflict of Interest: The authors declare no conflicts of interest.

Trichloroethylene (TCE) is an industrial solvent and widespread environmental contaminant. Although TCE exposure is prevalent, epidemiological studies of TCE exposure associations with adverse birth outcomes are inconclusive. Prior studies show that the TCE metabolite S-(1,2-dichlorovinyl)-L-cysteine (DCVC) exhibits toxicity in a placental cell line. In the current study, genome-wide gene expression and gene set enrichment analyses were used to identify novel genes and pathway alterations in the HTR-8/SVneo human trophoblast cell line and human placental villous explants treated with DCVC at concentrations relevant to human exposures. In the cells, concentration- and time-dependent effects were observed, as evidenced by the magnitude of altered gene expression after treatment with 20 µM DCVC versus 10 µM, and 12-h versus 6-h of treatment. Comparing the two models for the transcriptional response to 12-h 20 µM DCVC treatment, no differentially expressed genes reached significance in villous explants, whereas 301 differentially expressed genes were detected in HTR-8/SVneo cells compared with non-treated controls (FDR < 0.05 + LogFC > 0.35 [FC > 1.3]). GSEA revealed five upregulated enriched pathways in common between explants and cells (FDR < 0.05). Moreover, all 12-h DCVC treatment groups from both models contained upregulated pathways enriched for genes regulated by the ATF4 transcription factor. The overrepresentation of ATF4 regulation of differentially expressed genes indicated activation of the integrated stress response (ISR), a condition triggered by multiple stress stimuli, including the unfolded protein response. DCVC-induced ISR activation was confirmed by elevated eIF2α phosphorylation, ATF4 protein concentrations, and decreased global protein synthesis in HTR-8/SVneo cells. This study identifies a mechanism of DCVC-induced cytotoxicity by revealing the involvement of a specific stress signaling pathway.

Purpose of Review: This article introduces the roles of perinatal DNA methylation in human health and disease, highlights the challenges of tissue and cellular heterogeneity to studying DNA methylation, summarizes approaches to overcome these challenges, and offers recommendations in conducting research in environmental epigenetics., Recent Findings: Epigenetic modifications are essential for human development and are labile to environmental influences, especially during gestation. Epigenetic dysregulation is also a hallmark of multiple diseases. Environmental epigenetic studies routinely measure DNA methylation in readily available tissues. However, tissues and cell types exhibit specific epigenetic patterning and heterogeneity between samples complicates epigenetic studies. Failure to account for cell-type heterogeneity limits identification of biological mechanisms and biases study results. Tissue-level epigenetic measures represent a convolution of epigenetic signals from individual cell types. Tissue-specific epigenetics is an evolving field and the use of disease-affected target, surrogate, or multiple tissues has inherent trade-offs and affects inference. Likewise, experimental and bioinformatic approaches to accommodate cell-type heterogeneity have varying assumptions and inherent trade-offs that affect inference. The relationships between exposure, disease, tissue-level DNA methylation, cell type-specific DNA methylation, and cell-type heterogeneity must be carefully considered in study design and analysis. Causal diagrams can inform study design and analytic strategies. Properly addressing cell-type heterogeneity limits sources of potential bias, avoids misinterpretation of study results, and allows investigators to distinguish shifts in cell-type proportions from direct changes to cellular epigenetic programming, both of which provide insights into environmental disease etiology and aid development of novel methods for prevention and treatment.