Physiological development requires precise spatiotemporal regulation of cellular and molecular processes. Disruption of these key events can generate developmental toxicity in the form of teratogenesis or mortality. The mechanism behind many developmental toxicants remains unknown. While recent work has focused on the unfolded protein response (UPR), oxidative stress, and apoptosis in the pathogenesis of disease, few studies have addressed their relationship in developmental toxicity. Redox regulation, UPR, and apoptosis are essential for physiological development and can be disturbed by a variety of endogenous and exogenous toxicants to generate lethality and diverse malformations. This review examines the current knowledge of the role of oxidative stress, UPR, and apoptosis in physiological development as well as in developmental toxicity, focusing on studies and advances in vertebrates model systems.

Background: Trace metal concentrations may affect cardio-metabolic risk, but the role of prenatal exposure is unclear. We examined: 1) the relationship between blood metal concentrations during pregnancy and child cardio-metabolic risk factors; 2) overall effects of metals mixture (essential vs. nonessential); and 3) interactions between metals. Methods: We measured 11 metals in maternal 2 nd trimester whole blood in a prospective birth cohort in Mexico City. In children 4-6 years old, we measured body mass index (BMI), percent body fat, and blood pressure (N=609); and plasma hemoglobin A1C (HbA1c) , non-high density lipoprotein (HDL) cholesterol, triglycerides, leptin, and adiponectin (N=411). We constructed cardio-metabolic component scores using age-and sex-adjusted z-scores and averaged five scores to create a global risk score. We estimated linear associations of each metal with individual zscores and used Bayesian Kernel Machine Regression to assess metal mixtures and interactions.

Human milk plays a critical role in infant development and health, particularly in cognitive, immune, and cardiometabolic functions. Milk contains extracellular vesicles (EVs) that can transport biologically relevant cargo from mother to infant, including microRNAs (miRNAs). We aimed to characterize milk EV-miRNA profiles in a human population cohort, assess potential pathways and ontology, and investigate associations with maternal characteristics. We conducted the first study to describe the EV miRNA profile of human milk in 364 mothers from a population-based mother-infant cohort in the Faroe Islands using small RNA sequencing. We detected 1523 miRNAs with ≥ one read in 70% of samples. Using hierarchical clustering, we determined five EV-miRNA clusters, the top three consisting of 15, 27 and 67 miRNAs. Correlation coefficients indicated that the expression of many miRNAs within the top three clusters was highly correlated. Top-cluster human milk EV-miRNAs were involved in pathways enriched for the endocrine system, cellular community, neurodevelopment, and cancers. miRNA expression was associated with time to milk collection post-delivery, maternal body mass index, and maternal smoking, but not maternal parity. Future studies investigating determinants of human EV-miRNAs and associated health outcomes are needed to elucidate the role of human milk EV-miRNAs in health and disease.

Phthalates are associated with several adverse health outcomes, but few studies have evaluated phthalate exposures in Mexican populations, particularly pregnant women. Between 2007 and 2011, 948 pregnant women from Mexico City were recruited as part of the PROGRESS cohort. We quantified 17 metabolites of phthalates and phthalate alternatives in urine samples collected during the second and third trimesters and examined temporal trends of metabolites concentrations, within-person reproducibility, and relations of individual metabolites with sociodemographic, lifestyle, and occupational factors. Concentrations of mono-2-ethyl-5carboxypentyl terephthalate, a metabolite of the alternative phthalate di-2-ethylhexyl terephthalate,

Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) is a high-production volume organophosphate flame retardant widely used within the United States. Within zebrafish, initiation of TDCIPP exposure at 0.75 h post-fertilization (hpf) results in genome-wide alterations in methylation during cleavage (2 hpf) as well as epiboly delay or arrest (at higher concentrations) during late-blastula and early-gastrula (4–6 hpf). To determine whether these TDCIPP-induced effects were associated with impacts on the transcriptome, embryos were exposed to vehicle (0.1% DMSO) or 2 µM TDCIPP from 0.75 hpf to 6 hpf, and total RNA was extracted from triplicate embryo pools per treatment and hybridized onto duplicate Affymetrix Zebrafish Gene 1.0 ST Arrays per RNA sample. Based on transcriptome-wide profiling, TDCIPP resulted in a significant impact on biological processes involved in dorsoventral patterning and bone morphogenetic protein (BMP) signaling. Consistent with these responses, TDCIPP exposure also resulted in strongly dorsalized embryos by 24 hpf—a phenotype that mimicked the effects of dorsomorphin, a potent and selective BMP inhibitor. Moreover, the majority of dorsalized embryos were preceded by epiboly arrest at 6 hpf. Our microarray data also revealed that the expression of sizzled (szl)—a gene encoding a secreted Frizzled-related protein that limits BMP signaling—was significantly decreased by nearly 4-fold at 6 hpf. Therefore, we used a splice-blocking morpholino to test the hypothesis that knockdown of szl phenocopies TDCIPP-induced delays in epiboly progression. Interestingly, contrary to our hypothesis, injection of szl MOs did not affect epiboly progression but, similar to chordin (chd) morphants, resulted in mildly ventralized embryos by 24 hpf. Overall, our findings suggest that TDCIPP-induced epiboly delay may not be driven by decreased szl expression, and that TDCIPP-induced dorsalization may—similar to dorsomorphin—be due to interference with BMP signaling during early zebrafish development.

Tris(1,3-dichloro-2-propyl)phosphate (TDCIPP) is an organophosphate flame retardant that impacts zebrafish epiboly – an effect that may be associated with genome-wide hypomethylation. Using zebrafish as a model, the objectives of this study were to (1) quantify concentration-dependent impacts of TDCIPP on epiboly; (2) determine whether co-exposure with folic acid (FA) – a methyl donor – mitigates TDCIPP-induced impacts; and (3) using ten previously identified TDCIPP-susceptible loci, rely on bisulfite amplicon sequencing (BSAS) to monitor CpG methylation dynamics across multiple TDCIPP concentrations in the presence or absence of FA. Embryos were exposed to TDCIPP from 0.75 h post-fertilization (hpf) to 2, 4, 6, or 24 hpf in the presence or absence of 1 mM FA. Although TDCIPP delayed epiboly up to 3 h by 6 hpf and induced malformations by 24 hpf, FA was unable to mitigate TDCIPP-induced effects at all stages evaluated. Moreover, while no differences in global methylation were detected using a 5-methylcytosine (5-mC) DNA ELISA, BSAS revealed that TDCIPP-induced effects on CpG methylation were dependent on concentration and developmental stage, and that early effects on methylation do not persist despite continuous exposure. Our findings demonstrate that TDCIPP delays zebrafish epiboly, a phenotype that is preceded by complex, dynamic alterations in DNA methylation.

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Temperature is a key variable affecting the timing of amphibian metamorphosis from tadpoles to tetrapods, through the production and subsequent function of thyroid hormones (TH). Thyroid function can be impaired by environmental contaminants as well as temperature. Tadpoles can experience large temperature fluctuations in their habitats and many species are distributed in areas that may be impacted by agriculture. Diuron is a widely used herbicide detected in freshwater ecosystems and may impact endocrine function in aquatic organisms. We evaluated the influence of temperature (28 and 34 °C) on the action of diuron and its metabolite 3,4-dichloroaniline (3,4-DCA) on thyroid function and metamorphosis in tadpoles of Lithobates catesbeianus. Exposure to both compounds induced more pronounced changes in gene expression and plasma 3,3',5-triiodothyronine (T) concentrations in tadpoles treated at higher temperature. T concentrations were increased in tadpoles exposed to 200 ng/L of diuron at 34 °C and an acceleration of metamorphosis was observed for the same group. Transcriptomic responses included alteration of thyroid hormone induced bZip protein (thibz), deiodinases (dio2, dio3), thyroid receptors (trα, trβ) and Krüppel-like factor 9 (klf9), suggesting regulation by temperature on TH-gene expression. These results suggest that environmental temperature should be considered in risk assessments of environmental contaminants for amphibian species.