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Toxics
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Developmental Environmental Exposures, Epigenetics and Long-Term Health
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Developmental Environmental Exposures, Epigenetics and Long-Term Health

A special issue of Toxics (ISSN 2305-6304). This special issue belongs to the section "Reproductive and Developmental Toxicity".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 17465

Special Issue Editor

Dr. Laurie Svoboda

E-Mail Website
Guest Editor
Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI 48109-2029, USA
Interests: toxicology; developmental origins of health and disease; toxicoepigenetics; sex differences; metabolomics; stem cells; cardiovascular disease; nutrient–toxicant interactions

Special Issue Information

Dear Colleagues,

It is increasingly evident that environmental exposures during critical windows of development can impact human health across one’s lifespan. Developmental exposures linked to adverse health effects include heavy metals (lead, cadmium, arsenic), endocrine disruptors (phthalates, bisphenols, per- and polyfluoroalkyl substances (PFAS)), air pollutants (tobacco smoke, ozone, particulate matter) and radiation. Normal development is governed by widespread epigenomic reprogramming in the somatic cells and primordial germ cells of the developing embryo. This reprogramming includes changes in DNA methylation, DNA hydroxymethylation, chromatin modification/structure, and expression/function of noncoding RNAs. Epigenetic changes continue during the postnatal period, early childhood, and adolescence. An important mechanism by which early environmental exposures may affect long-term health is through interfering with these critical developmental processes. The effects of environmental agents on epigenomic programming during critical periods of development, and the implications these changes have for health across the lifespan, are incompletely understood.

In this Special Issue, we invite contributions (original articles, reviews, and communications) that address these important research questions. These include mechanistic studies conducted in a variety of models (animal, cell culture, human tissues), as well as human epidemiologic studies. Of particular interest are studies that address the sex-specific effects of develomental environmental exposures on the epigenome and health.

Dr. Laurie Svoboda
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • developmental origins of health and disease (DOHaD)
  • epigenetics
  • toxicoepigenetics
  • DNA methylation
  • DNA hydroxymethylation
  • chromatin
  • environmental health

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Published Papers (6 papers)

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Research

23 pages, 3303 KiB  
Article
Perinatal Lead Exposure Promotes Sex-Specific Epigenetic Programming of Disease-Relevant Pathways in Mouse Heart
by Laurie K. Svoboda, Kai Wang, Jaclyn M. Goodrich, Tamara R. Jones, Justin A. Colacino, Karen E. Peterson, Martha M. Tellez-Rojo, Maureen A. Sartor and Dana C. Dolinoy
Toxics 2023, 11(1), 85; https://doi.org/10.3390/toxics11010085 - 16 Jan 2023
Cited by 6 | Viewed by 2585
Abstract
Environmental contaminants such as the metal lead (Pb) are associated with cardiovascular disease, but the underlying molecular mechanisms are poorly understood. In particular, little is known about how exposure to Pb during early development impacts the cardiac epigenome at any point across the [...] Read more.
Environmental contaminants such as the metal lead (Pb) are associated with cardiovascular disease, but the underlying molecular mechanisms are poorly understood. In particular, little is known about how exposure to Pb during early development impacts the cardiac epigenome at any point across the life course and potential differences between sexes. In a mouse model of human-relevant perinatal exposures, we utilized RNA-seq and Enhanced Reduced Representation Bisulfite Sequencing (ERRBS) to investigate the effects of Pb exposure during gestation and lactation on gene expression and DNA methylation, respectively, in the hearts of male and female mice at weaning. For ERRBS, we identified differentially methylated CpGs (DMCs) or differentially methylated 1000 bp regions (DMRs) based on a minimum absolute change in methylation of 10% and an FDR < 0.05. For gene expression data, an FDR < 0.05 was considered significant. No individual genes met the FDR cutoff for gene expression; however, we found that Pb exposure leads to significant changes in the expression of gene pathways relevant to cardiovascular development and disease. We further found that Pb promotes sex-specific changes in DNA methylation at hundreds of gene loci (280 DMCs and 99 DMRs in males, 189 DMCs and 121 DMRs in females), and pathway analysis revealed that these CpGs and regions collectively function in embryonic development. In males, differential methylation also occurred at genes related to immune function and metabolism. We then investigated whether genes exhibiting differential methylation at weaning were also differentially methylated in hearts from a cohort of Pb-exposed mice at adulthood. We found that a single gene, Galnt2, showed differential methylation in both sexes and time points. In a human cohort investigating the influence of prenatal Pb exposure on the epigenome, we also observed an inverse association between first trimester Pb concentrations and adolescent blood leukocyte DNA methylation at a locus in GALNT2, suggesting that this gene may represent a biomarker of Pb exposure across species. Together, these data, across two time points in mice and in a human birth cohort study, collectively demonstrate that Pb exposure promotes sex-specific programming of the cardiac epigenome, and provide potential mechanistic insight into how Pb causes cardiovascular disease. Full article
(This article belongs to the Special Issue Developmental Environmental Exposures, Epigenetics and Long-Term Health)
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13 pages, 1963 KiB  
Article
Effects of Daily Peat Smoke Exposure on Present and Next Generations
by Vera A. Vokina, Larisa M. Sosedova, Mikhail A. Novikov, Evgeniy A. Titov, Elizaveta S. Andreeva and Viktor S. Rukavishnikov
Toxics 2022, 10(12), 750; https://doi.org/10.3390/toxics10120750 - 1 Dec 2022
Cited by 2 | Viewed by 1614
Abstract
This study aimed to follow the neurotoxic effect of peat smoke on adult outbred rats and its influence on central nervous system (CNS) parameters in first-generation offspring. Under experimental conditions, exposure to peat smoke was carried out on adult male Wistar rats for [...] Read more.
This study aimed to follow the neurotoxic effect of peat smoke on adult outbred rats and its influence on central nervous system (CNS) parameters in first-generation offspring. Under experimental conditions, exposure to peat smoke was carried out on adult male Wistar rats for 24 h. After the end of the exposure, an open field test (OFT), electroencephalography (EEG), and histological analysis of the testes and brains of smoke-exposed males were performed, after which they were mated with intact females to obtain F1 offspring. Stillbirth, neonatal mortality, and body weight at 4, 7, 14, and 21 postnatal days, as well as behavior in the OFT and EEG parameters during puberty (3 months), were assessed. The results of the examination of F0 males showed a significant increase in motor activity and anxiety in the open field test and a violation of EEG parameters. Histopathologically, peat smoke caused a sharp increase in shadow cells (homogeneous cells with pale-stained cytoplasm, in which the cell and nuclear membranes are not visualized) and degeneratively altered neurons in the brain; we found no changes in the testicles. Peat smoke exposure during preconception did not affect neonatal mortality and weight gain in F1 offspring. Adult females born to peat-smoke-exposed males showed an increase in locomotor activity, and the behavior of adult F1 males did not differ from the control. In F1 males, a statistically significant increase in slow-wave activity indices in the delta band was observed. Full article
(This article belongs to the Special Issue Developmental Environmental Exposures, Epigenetics and Long-Term Health)
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11 pages, 2029 KiB  
Article
Transient Post-Natal Exposure to Xenoestrogens Induces Long-Term Alterations in Cardiac Calcium Signaling
by Cassandra Tabasso, Marie-Pauline Frossard, Camille Ducret, Hassib Chehade, Claire Mauduit, Mohamed Benahmed, Umberto Simeoni and Benazir Siddeek
Toxics 2022, 10(3), 102; https://doi.org/10.3390/toxics10030102 - 23 Feb 2022
Viewed by 2517
Abstract
Today, non-communicable disorders are widespread worldwide. Among them, cardiovascular diseases represent the main cause of death. At the origin of these diseases, exposure to challenges during developmental windows of vulnerability (peri-conception, in utero, and early infancy periods) have been incriminated. Among the challenges [...] Read more.
Today, non-communicable disorders are widespread worldwide. Among them, cardiovascular diseases represent the main cause of death. At the origin of these diseases, exposure to challenges during developmental windows of vulnerability (peri-conception, in utero, and early infancy periods) have been incriminated. Among the challenges that have been described, endocrine disruptors are of high concern because of their omnipresence in the environment. Worrisomely, since birth, children are exposed to a significant number of endocrine disruptors. However, the role of such early exposure on long-term cardiac health is poorly described. In this context, based on a model of rats exposed postnatally and transiently to an estrogenic compound prototype (estradiol benzoate, EB), we aimed to delineate the effects on the adult heart of such transient early exposure to endocrine disruptors and identify the underlying mechanisms involved in the potential pathogenesis. We found that this transient post-natal exposure to EB induced cardiac hypertrophy in adulthood, with increased cardiomyocyte size. The evaluation of cardiac calcium signaling, through immunoblot approaches, highlighted decreased expression of the sarcoplasmic reticulum calcium ATPase 2 (SERCA2) and decreased Nuclear Factor of Activated T Cells (NFAT3) phosphorylation as a potential underlying mechanism of cardiac hypertrophy. Furthermore, the treatment of cardiomyocytes with EB in vitro induced a decrease in SERCA2 protein levels. Overall, our study demonstrates that early transient exposure to EB induces permanent cardiac alterations. Together, our data highlight SERCA2 down-regulation as a potential mechanism involved in the cardiac pathogenesis induced by EB. These results suggest programming of adult heart dysfunctions such as arrhythmia and heart failures by early exposure to endocrine disruptors and could open new perspectives for treatment and prevention. Full article
(This article belongs to the Special Issue Developmental Environmental Exposures, Epigenetics and Long-Term Health)
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16 pages, 733 KiB  
Article
Prenatal Particulate Matter Exposure Is Associated with Saliva DNA Methylation at Age 15: Applying Cumulative DNA Methylation Scores as an Exposure Biomarker
by Kelly M. Bakulski, Jonah D. Fisher, John F. Dou, Arianna Gard, Lisa Schneper, Daniel A. Notterman, Erin B. Ware and Colter Mitchell
Toxics 2021, 9(10), 262; https://doi.org/10.3390/toxics9100262 - 13 Oct 2021
Cited by 8 | Viewed by 2784
Abstract
Exposure in utero to particulate matter (PM2.5 and PM10) is associated with maladaptive health outcomes. Although exposure to prenatal PM2.5 and PM10 has cord blood DNA methylation signatures at birth, signature persistence into childhood and saliva cross-tissue applicability has not been tested. In [...] Read more.
Exposure in utero to particulate matter (PM2.5 and PM10) is associated with maladaptive health outcomes. Although exposure to prenatal PM2.5 and PM10 has cord blood DNA methylation signatures at birth, signature persistence into childhood and saliva cross-tissue applicability has not been tested. In the Fragile Families and Child Wellbeing Study, a United States 20-city birth cohort, average residential PM2.5 and PM10 during the three months prior to birth was estimated using air quality monitors with inverse distance weighting. Saliva DNA methylation at ages 9 (n = 749) and 15 (n = 793) was measured using the Illumina HumanMethylation 450 k BeadArray. Cumulative DNA methylation scores for particulate matter were estimated by weighting participant DNA methylation at each site by independent meta-analysis effect estimates and standardizing the sums. Using a mixed-effects regression analysis, we tested the associations between cumulative DNA methylation scores at ages 9 and 15 and PM exposure during pregnancy, adjusted for child sex, age, race/ethnicity, maternal income-to-needs ratio, nonmartial birth status, and saliva cell-type proportions. Our study sample was 50.5% male, 56.3% non-Hispanic Black, and 19.8% Hispanic, with a median income-to-needs ratio of 1.4. Mean exposure levels for PM2.5 were 27.9 μg/m3/day (standard deviation: 7.0; 23.7% of observations exceeded safety standards) and for PM10 were 15.0 μg/m3/day (standard deviation: 3.1). An interquartile range increase in PM2.5 exposure (10.73 μg/m3/day) was associated with a −0.0287 standard deviation lower cumulative DNA methylation score for PM2.5 (95% CI: −0.0732, 0.0158, p = 0.20) across all participants. An interquartile range increase in PM10 exposure (3.20 μg/m3/day) was associated with a −0.1472 standard deviation lower cumulative DNA methylation score for PM10 (95% CI: −0.3038, 0.0095, p = 0.06) across all participants. The PM10 findings were driven by the age 15 subset where an interquartile range increase in PM10 exposure was associated with a −0.024 standard deviation lower cumulative DNA methylation score for PM10 (95% CI: −0.043, −0.005, p = 0.012). Findings were robust to adjustment for PM exposure at ages 1 and 3. In utero PM10-associated DNA methylation differences were identified at age 15 in saliva. Benchmarking the timing and cell-type generalizability is critical for epigenetic exposure biomarker assessment. Full article
(This article belongs to the Special Issue Developmental Environmental Exposures, Epigenetics and Long-Term Health)
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7 pages, 240 KiB  
Article
Elimination of Intravenous Di-2-Ethylhexyl Phthalate Exposure Abrogates Most Neonatal Hypertension in Premature Infants with Bronchopulmonary Dysplasia
by Randall Jenkins, Katia Farnbach and Sandra Iragorri
Toxics 2021, 9(4), 75; https://doi.org/10.3390/toxics9040075 - 2 Apr 2021
Cited by 9 | Viewed by 2643
Abstract
(1) Background: The incidence of hypertension in very low birthweight (VLBW) infants in a single neonatal intensive care unit (NICU) dropped markedly during a 2-year period when the IV fluid (IVF) in both the antenatal unit and the NICU temporarily changed to a [...] Read more.
(1) Background: The incidence of hypertension in very low birthweight (VLBW) infants in a single neonatal intensive care unit (NICU) dropped markedly during a 2-year period when the IV fluid (IVF) in both the antenatal unit and the NICU temporarily changed to a di-2-ethylhexyl phthalate (DEHP)-free formulation. The objective of the current report is to document this observation and demonstrate the changes in incidence of hypertension were not associated with the variation in risk factors for hypertension; (2) Methods: The charts of all VLBW infants born in a single NICU during a 7-year span were reviewed. This time includes 32 months of baseline, 20 months of DEHP-free IVF, 20 months of IVF DEHP re-exposure, and two 4-month washout intervals. The group of interest was limited to VLBW infants with bronchopulmonary dysplasia (BPD). Chi-square analysis was used to compare incidence of hypertension among periods. Vermont Oxford NICU Registry data were examined for variation in maternal and neonatal risk factors for hypertension; Results: Incidence of hypertension in VLBW infants with BPD decreased from 7.7% (baseline) to 1.4% when IVF was DEHP-free, rising back to 10.1% when DEHP-containing IVF returned to use. Risk factors for neonatal hypertension were stable across the 3 study periods in the NICU’s group of VLBW infants; (3) Conclusions: Serendipitous removal of IVF containing DEHP resulted in near elimination of hypertension in one NICU—an effect entirely reversed after the same brand of DEHP-containing IVF returned to clinical use. These results suggest that DEHP exposure from IVF plays a major role in neonatal hypertension. Full article
(This article belongs to the Special Issue Developmental Environmental Exposures, Epigenetics and Long-Term Health)
11 pages, 1978 KiB  
Article
Paternal Biomass Smoke Exposure in Rats Produces Behavioral and Cognitive Alterations in the Offspring
by Larisa M. Sosedova, Vera A. Vokina, Mikhail A. Novikov, Viktor S. Rukavishnikov, Elizaveta S. Andreeva, Olga M. Zhurba and Anton N. Alekseenko
Toxics 2021, 9(1), 3; https://doi.org/10.3390/toxics9010003 - 31 Dec 2020
Cited by 13 | Viewed by 4280
Abstract
Particular concern at the present stage is the health effects of wildfires’ smoke. The aim of the study was to determine the impact of paternal biomass-smoke exposure on offspring’s behavior and cognitive abilities. Male rats were exposed to biomass smoke for four hours/day, five [...] Read more.
Particular concern at the present stage is the health effects of wildfires’ smoke. The aim of the study was to determine the impact of paternal biomass-smoke exposure on offspring’s behavior and cognitive abilities. Male rats were exposed to biomass smoke for four hours/day, five days/week, for four weeks. Average concentration of carbon monoxide and particulate matter of 2.5 μm PM2.5 in the chamber during exposure were 28.7 ± 5.3 mg/m3 and 1.9 ± 0.5 mg/m3, respectively. At the same time, high concentrations of furfural and acetaldehyde were detected in the air environment of the exposure chambers. Offspring was obtained by mating of experimental males with untreated females, immediately after the end of the exposure and after 60 days (long-term period). Offspring were tested by using the Morris water maze and open field at three months of age. Male and female offspring born by mating immediately after exposure demonstrated decreased exploratory behavior, locomotor activity, and spatial navigation, as well as increased anxiety levels. Locomotor and exploratory activity in rats of both sexes from progeny obtained after long-term exposure to smoke had no statistically significant differences when compared to the control; however, the females showed a high level of anxiety and impaired cognitive functions. The recovery period after biomass-smoke intoxication, comparable in duration of spermatogenesis in rats, was an important factor in reducing the risk of developing central nervous system (CNS) disorders in offspring. Full article
(This article belongs to the Special Issue Developmental Environmental Exposures, Epigenetics and Long-Term Health)
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