scholarly journals From Extrapolation to Precision Chemical Hazard Assessment: The Ecdysone Receptor Case Study

Toxics ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 6
Author(s):  
Raquel Ruivo ◽  
João Sousa ◽  
Teresa Neuparth ◽  
Olivier Geffard ◽  
Arnaud Chaumot ◽  
...  
Keyword(s):  
Hazard Assessment ◽  
Functional Characterization ◽  
Chemical Exposure ◽  
Environmental Chemicals ◽  
Current Evidence ◽  
Ecdysone Receptor ◽  
Environmental Chemical ◽  
Chemical Action ◽  
Assessment Strategies

Hazard assessment strategies are often supported by extrapolation of damage probabilities, regarding chemical action and species susceptibilities. Yet, growing evidence suggests that an adequate sampling of physiological responses across a representative taxonomic scope is of paramount importance. This is particularly relevant for Nuclear Receptors (NR), a family of transcription factors, often triggered by ligands and thus, commonly exploited by environmental chemicals. Within NRs, the ligand-induced Ecdysone Receptor (EcR) provides a remarkable example. Long regarded as arthropod specific, this receptor has been extensively targeted by pesticides, seemingly innocuous to non-target organisms. Yet, current evidence clearly suggests a wider presence of EcR orthologues across metazoan lineages, with unknown physiological consequences. Here, we address the state-of-the-art regarding the phylogenetic distribution and functional characterization of metazoan EcRs and provide a critical analysis of the potential disruption of such EcRs by environmental chemical exposure. Using EcR as a case study, hazard assessment strategies are also discussed in view of the development of a novel “precision hazard assessment paradigm.

scholarly journals Environmental Chemical Diethylhexyl Phthalate Alters Intestinal Microbiota Community Structure and Metabolite Profile in Mice

mSystems ◽  
2019 ◽  
Vol 4 (6) ◽  
Author(s):  
Ming Lei ◽  
Rani Menon ◽  
Sara Manteiga ◽  
Nicholas Alden ◽  
Carrie Hunt ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Neurodevelopmental Disorders ◽  
Developmental Disorders ◽  
Chemical Exposure ◽  
Metabolite Profile ◽  
Environmental Chemicals ◽  
Toxic Metabolite ◽  
Environmental Chemical ◽  
Diethylhexyl Phthalate

ABSTRACT Exposure to environmental chemicals during windows of development is a potentially contributing factor in gut microbiota dysbiosis and linked to chronic diseases and developmental disorders. We used a community-level model of microbiota metabolism to investigate the effects of diethylhexyl phthalate (DEHP), a ubiquitous plasticizer implicated in neurodevelopmental disorders, on the composition and metabolite outputs of gut microbiota in young mice. Administration of DEHP by oral gavage increased the abundance of Lachnoclostridium, while decreasing Clostridium sensu stricto. Addition of DEHP to in vitro-cultured cecal microbiota increased the abundance of Paenibacillus and Lachnoclostridium. Untargeted metabolomics showed that DEHP broadly altered the metabolite profile in the culture. Notably, DEHP enhanced the production of p-cresol while inhibiting butyrate synthesis. Metabolic model-guided correlation analysis indicated that the likely sources of p-cresol are Clostridium species. Monoculture of Lachnoclostridium bolteae confirmed that it is capable of producing p-hydroxyphenylacetic acid, the immediate precursor of p-cresol, and that the species’ growth is enhanced upon DEHP exposure. Taken together, these findings suggest a model where DEHP increases production of p-cresol, a bacterial metabolite linked with neurodevelopmental disorders, by expanding the abundance of species that synthesize the metabolite’s precursor. IMPORTANCE Several previous studies have pointed to environmental chemical exposure during windows of development as a contributing factor in neurodevelopmental disorders and correlated these disorders with microbiota dysbiosis; however, little is known about how the chemicals specifically alter the microbiota to interfere with development. The findings reported in this paper unambiguously establish that a pollutant linked with neurodevelopmental disorders can directly modify the microbiota to promote the production of a potentially toxic metabolite (p-cresol) that has also been correlated with neurodevelopmental disorders. Furthermore, we used a novel modeling strategy to identify the responsible enzymes and bacterial sources of this metabolite. To the best of our knowledge, the present study is the first to characterize the functional consequence of phthalate exposure on a developed microbiota. Our results suggest that specific bacterial pathways could be developed as diagnostic and therapeutic targets against health risks posed by ingestion of environmental chemicals.

scholarly journals PCB126 exposure revealed alterations in m6A RNA modifications in transcripts associated with AHR activation

2020 ◽  
Author(s):  
Neelakanteswar Aluru ◽  
Sibel I Karchner
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Gene Expression Profiles ◽  
Chemical Exposure ◽  
Environmental Chemicals ◽  
Rna Modifications ◽  
Environmental Chemical ◽  
Stop Codons ◽  
Developmental Gene Expression

AbstractChemical modifications of proteins, DNA and RNA moieties play critical roles in regulating gene expression. Emerging evidence suggests these RNA modifications (epitranscriptomics) have substantive roles in basic biological processes. One of the most common modifications in mRNA and noncoding RNAs is N6-methyladenosine (m6A). In a subset of mRNAs, m6A sites are preferentially enriched near stop codons, in 3’ UTRs, and within exons, suggesting an important role in the regulation of mRNA processing and function including alternative splicing and gene expression. Very little is known about the effect of environmental chemical exposure on m6A modifications. As many of the commonly occurring environmental contaminants alter gene expression profiles and have detrimental effects on physiological processes, it is important to understand the effects of exposure on this important layer of gene regulation. Hence, the objective of this study was to characterize the acute effects of developmental exposure to PCB126, an environmentally relevant dioxin-like PCB, on m6A methylation patterns. We exposed zebrafish embryos to PCB126 for 6 hours starting from 72 hours post-fertilization and profiled m6A RNA using methylated RNA immunoprecipitation followed by sequencing (MeRIP-seq). Our analysis revealed 117 and 217 m6A peaks in the DMSO and PCB126 samples (FDR 5%), respectively. The majority of the peaks were preferentially located around the 3’UTR and stop codons. Statistical analysis revealed 15 m6A marked transcripts to be differentially methylated by PCB126 exposure. These include transcripts that are known to be activated by AHR agonists (e.g., ahrra, tiparp, nfe2l2b) as well as others that are important for normal development (vgf, cebpd, foxi1). These results suggest that environmental chemicals such as dioxin-like PCBs could affect developmental gene expression patterns by altering m6A levels. Further studies are necessary to understand the functional consequences of exposure-associated alterations in m6A levels.

scholarly journals PCB126 Exposure Revealed Alterations in m6A RNA Modifications in Transcripts Associated With AHR Activation

2020 ◽  
Author(s):  
Neelakanteswar Aluru ◽  
Sibel I Karchner
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Gene Expression Profiles ◽  
Chemical Exposure ◽  
Environmental Chemicals ◽  
Rna Modifications ◽  
Environmental Chemical ◽  
Stop Codons ◽  
Developmental Gene Expression

Abstract Chemical modifications of proteins, DNA, and RNA moieties play critical roles in regulating gene expression. Emerging evidence suggests the RNA modifications (epitranscriptomics) have substantive roles in basic biological processes. One of the most common modifications in mRNA and noncoding RNAs is N6-methyladenosine (m6A). In a subset of mRNAs, m6A sites are preferentially enriched near stop codons, in 3′ UTRs, and within exons, suggesting an important role in the regulation of mRNA processing and function including alternative splicing and gene expression. Very little is known about the effect of environmental chemical exposure on m6A modifications. As many of the commonly occurring environmental contaminants alter gene expression profiles and have detrimental effects on physiological processes, it is important to understand the effects of exposure on this important layer of gene regulation. Hence, the objective of this study was to characterize the acute effects of developmental exposure to PCB126, an environmentally relevant dioxin-like PCB, on m6A methylation patterns. We exposed zebrafish embryos to PCB126 for 6 h starting from 72 h post fertilization and profiled m6A RNA using methylated RNA immunoprecipitation followed by sequencing (MeRIP-seq). Our analysis revealed 117 and 217 m6A peaks in the DMSO and PCB126 samples (false discovery rate 5%), respectively. The majority of the peaks were preferentially located around the 3′ UTR and stop codons. Statistical analysis revealed 15 m6A marked transcripts to be differentially methylated by PCB126 exposure. These include transcripts that are known to be activated by AHR agonists (eg, ahrra, tiparp, nfe2l2b) as well as others that are important for normal development (vgf, cebpd, sned1). These results suggest that environmental chemicals such as dioxin-like PCBs could affect developmental gene expression patterns by altering m6A levels. Further studies are necessary to understand the functional consequences of exposure-associated alterations in m6A levels.

scholarly journals Lipophilic chemical exposure as a cause of cardiovascular disease

2013 ◽  
Vol 6 (2) ◽  
pp. 55-62 ◽  
Author(s):  
Harold I. Zeliger
Keyword(s):  
Cardiovascular Disease ◽  
Developmental Disorders ◽  
Metabolic Disorders ◽  
Chemical Properties ◽  
Chemical Exposure ◽  
Environmental Chemicals ◽  
Low Molecular Weight ◽  
Endocrine Disorders ◽  
Environmental Chemical

Abstract Environmental chemical exposure has been linked to numerous diseases in humans. These diseases include cancers; neurological and neurodegenerative diseases; metabolic disorders including type 2 diabetes, metabolic syndrome and obesity; reproductive and developmental disorders; and endocrine disorders. Many studies have associated the link between exposures to environmental chemicals and cardiovascular disease (CVD). These chemicals include persistent organic pollutants (POPs); the plastic exudates bisphenol A and phthalates; low molecular weight hydrocarbons (LMWHCs); and poly nuclear aromatic hydrocarbons (PAHs). Here it is reported that though the chemicals reported on differ widely in chemical properties and known points of attack in humans, a common link exists between them. All are lipophilic species that are found in serum. Environmentally induced CVD is related to total lipophilic chemical load in the blood. Lipophiles serve to promote the absorption of otherwise not absorbed toxic hydrophilic species that promote CVD.

scholarly journals Bisphenol A Is More Potent than Phthalate Metabolites in Reducing Pancreatic β-Cell Function

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Nina Mickelson Weldingh ◽  
Lena Jørgensen-Kaur ◽  
Rune Becher ◽  
Jørn A. Holme ◽  
Johanna Bodin ◽  
...  
Keyword(s):  
Cell Death ◽  
Insulin Secretion ◽  
Bisphenol A ◽  
Cell Function ◽  
Chemical Exposure ◽  
Environmental Chemicals ◽  
Environmental Chemical ◽  
Simultaneous Exposure ◽  
Phthalate Metabolites ◽  
Β Cell Function

Bisphenol A (BPA) and phthalates are common environmental contaminants that have been proposed to influence incidence and development of types 1 and 2 diabetes. Thus, effects of BPA and three phthalate metabolites (monoisobutyl phthalate (MiBP), mono-n-butyl phthalate (MnBP), and mono-(2-ethylhexyl) phthalate (MEHP)) were studied in the pancreatic β-cell line INS-1E, after 2–72 h of exposure to 5–500 μM. Three endpoints relevant to accelerated development of types 1 or 2 diabetes were investigated: β-cell viability, glucose-induced insulin secretion, and β-cell susceptibility to cytokine-induced cell death. BPA and the phthalate metabolites reduced cellular viability after 72 h of exposure, with BPA as the most potent chemical. Moreover, BPA, MEHP, and MnBP increased insulin secretion after 2 h of simultaneous exposure to chemicals and glucose, with potency BPA > MEHP > MnBP. Longer chemical exposures (24–72 h) showed no consistent effects on glucose-induced insulin secretion, and none of the environmental chemicals affected susceptibility to cytokine-induced cell death. Overall, BPA was more potent than the investigated phthalate metabolites in affecting insulin secretion and viability in the INS-1E pancreatic β-cells. In contrast to recent literature, concentrations with relevance to human exposures (1–500 nM) did not affect the investigated endpoints, suggesting that this experimental model displayed relatively low sensitivity to environmental chemical exposure.

scholarly journals Environmental chemical diethylhexyl phthalate alters intestinal microbiota community structure and metabolite profile in mice

2019 ◽  
Author(s):  
Ming Lei ◽  
Rani Menon ◽  
Sara Manteiga ◽  
Nicholas Alden ◽  
Carrie Hunt ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Neurodevelopmental Disorders ◽  
Developmental Disorders ◽  
Chemical Exposure ◽  
Metabolite Profile ◽  
Environmental Chemicals ◽  
Toxic Metabolite ◽  
Environmental Chemical ◽  
Diethylhexyl Phthalate

AbstractExposure to environmental chemicals during windows of development is a potentially contributing factor in gut microbiota dysbiosis, and linked to chronic diseases and developmental disorders. We used a community-level model of microbiota metabolism to investigate the effects of diethylhexyl phthalate (DEHP), a ubiquitous plasticizer implicated in neurodevelopmental disorders, on the composition and metabolite outputs of gut microbiota in young mice. Administration of DEHP by oral gavage increased the abundance ofLachnoclostridum, while decreasingAkkermansia, Odoribacter, andClostridium sensu stricto. Addition of DEHP toin vitrocultured cecal microbiota increased the abundance ofAlistipes, Paenibacillus, andLachnoclostridium. Untargeted metabolomics showed that DEHP broadly altered the metabolite profile in the culture. Notably, DEHP enhanced the production ofp-cresol, while inhibiting butyrate synthesis. Metabolic model-guided correlation analysis indicated that the likely sources ofp-cresol areClostridiumspecies. Our results suggest that DEHP can directly modify the microbiota to affect production of bacterial metabolites linked with neurodevelopmental disorders.ImportanceSeveral previous studies have pointed to environmental chemical exposure during windows of development as a contributing factor in neurodevelopmental disorders, and correlated these disorders with microbiota dysbiosis, little is known about how the chemicals specifically alter the microbiota to interfere with development. The findings reported in this paper unambiguously establish that a pollutant linked with neurodevelopmental disorders can directly modify the microbiota to promote the production of a potentially toxic metabolite (p-cresol) that has also been correlated with neurodevelopmental disorders. Further, we use a novel modeling strategy to identify the responsible enzymes and bacterial sources of this metabolite. To the best of our knowledge, the present study is the first to characterize the functional consequence of phthalate exposure on a developed microbiota. Our results suggest that specific bacterial pathways could be developed as diagnostic and therapeutic targets against health risks posed by ingestion of environmental chemicals.

scholarly journals Adverse Impact of Environmental Chemicals on Developmental Origins of Kidney Disease and Hypertension

2021 ◽  
Vol 12 ◽  
Author(s):  
Chien-Ning Hsu ◽  
You-Lin Tain
Keyword(s):  
Kidney Disease ◽  
Animal Studies ◽  
Kidney Development ◽  
Renin Angiotensin System ◽  
Chemical Exposure ◽  
Environmental Chemicals ◽  
Developmental Origins ◽  
Environmental Chemical ◽  
Pregnancy And Lactation ◽  
Exposure During Pregnancy

Chronic kidney disease (CKD) and hypertension are becoming a global health challenge, despite developments in pharmacotherapy. Both diseases can begin in early life by so-called “developmental origins of health and disease” (DOHaD). Environmental chemical exposure during pregnancy can affect kidney development, resulting in renal programming. Here, we focus on environmental chemicals that pregnant mothers are likely to be exposed, including dioxins, bisphenol A (BPA), phthalates, per- and polyfluoroalkyl substances (PFAS), polycyclic aromatic hydrocarbons (PAH), heavy metals, and air pollution. We summarize current human evidence and animal models that supports the link between prenatal exposure to environmental chemicals and developmental origins of kidney disease and hypertension, with an emphasis on common mechanisms. These include oxidative stress, renin-angiotensin system, reduced nephron numbers, and aryl hydrocarbon receptor signaling pathway. Urgent action is required to identify toxic chemicals in the environment, avoid harmful chemicals exposure during pregnancy and lactation, and continue to discover other potentially harmful chemicals. Innovation is also needed to identify kidney disease and hypertension in the earliest stage, as well as translating effective reprogramming interventions from animal studies into clinical practice. Toward DOHaD approach, prohibiting toxic chemical exposure and better understanding of underlying mechanisms, we have the potential to reduce global burden of kidney disease and hypertension.

scholarly journals Triclosan Exposure is Associated with Rapid Restructuring of the Microbiome in Adult Zebrafish

2016 ◽  
Author(s):  
Christopher A. Gaulke ◽  
Carrie L. Barton ◽  
Sarah Proffitt ◽  
Robert L. Tanguay ◽  
Thomas J. Sharpton
Keyword(s):  
Microbial Communities ◽  
Gut Microbiome ◽  
Control Diet ◽  
Experimental System ◽  
Chemical Exposure ◽  
Amplicon Sequencing ◽  
Environmental Chemicals ◽  
Adult Zebrafish ◽  
Environmental Chemical ◽  
Ecological Dynamics

AbstractGrowing evidence indicates that disrupting the microbial community that comprises the intestinal tract, known as the gut microbiome, can contribute to the development or severity of disease. As a result, it is important to discern the agents responsible for microbiome disruption. While animals are frequently exposed to a diverse array of environmental chemicals, little is known about their effects on gut microbiome stability and structure. Here, we demonstrate how zebrafish can be used to glean insight into the effects of environmental chemical exposure on the structure and ecological dynamics of the gut microbiome. Specifically, we exposed forty-five adult zebrafish to triclosan-laden food for four or seven days or a control diet, and analyzed their microbial communities using 16S rRNA amplicon sequencing. Triclosan exposure was associated with rapid shifts in microbiome structure and diversity. We find evidence that several operational taxonomic units (OTUs) associated with the family Enterobacteriaceae appear to be susceptible to triclosan exposure, while OTUs associated with the genus Pseudomonas appeared to be more resilient and resistant to exposure. We also found that triclosan exposure is associated with topological alterations to microbial interaction networks and results in an overall increase in the number of negative interactions per microbe in these networks. Together these data indicate that triclosan exposure results in altered composition and ecological dynamics of microbial communities in the gut. Our work demonstrates that because zebrafish afford rapid and inexpensive interrogation of a large number of individuals, it is a useful experimental system for the discovery of the gut microbiome’s interaction with environmental chemicals.

scholarly journals Can Exposure to Environmental Chemicals Increase the Risk of Diabetes Type 1 Development?

2015 ◽  
Vol 2015 ◽  
pp. 1-19 ◽  
Author(s):  
Johanna Bodin ◽  
Lars Christian Stene ◽  
Unni Cecilie Nygaard
Keyword(s):  
Environmental Factors ◽  
Immune Cell ◽  
Pancreatic Beta Cell ◽  
Environmental Pollutants ◽  
Chemical Exposure ◽  
Environmental Chemicals ◽  
Negative Effects ◽  
Environmental Chemical ◽  
Cell Functions

Type 1 diabetes mellitus (T1DM) is an autoimmune disease, where destruction of beta-cells causes insulin deficiency. The incidence of T1DM has increased in the last decades and cannot entirely be explained by genetic predisposition. Several environmental factors are suggested to promote T1DM, like early childhood enteroviral infections and nutritional factors, but the evidence is inconclusive. Prenatal and early life exposure to environmental pollutants like phthalates, bisphenol A, perfluorinated compounds, PCBs, dioxins, toxicants, and air pollutants can have negative effects on the developing immune system, resulting in asthma-like symptoms and increased susceptibility to childhood infections. In this review the associations between environmental chemical exposure and T1DM development is summarized. Although information on environmental chemicals as possible triggers for T1DM is sparse, we conclude that it is plausible that environmental chemicals can contribute to T1DM development via impaired pancreatic beta-cell and immune-cell functions and immunomodulation. Several environmental factors and chemicals could act together to trigger T1DM development in genetically susceptible individuals, possibly via hormonal or epigenetic alterations. Further observational T1DM cohort studies and animal exposure experiments are encouraged.

scholarly journals Putative Mechanisms of Environmental Chemical–Induced Steatosis

2012 ◽  
Vol 31 (6) ◽  
pp. 551-563 ◽  
Author(s):  
J. Phillip Kaiser ◽  
John C. Lipscomb ◽  
Scott C. Wesselkamper
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Pathological Condition ◽  
Initial Step ◽  
Chemical Exposure ◽  
Environmental Chemicals ◽  
Environmental Chemical ◽  
Integrated Risk ◽  
The Us

Liver disease is a major health issue characterized by several pathological changes, with steatosis (fatty liver) representing a common initial step in its pathogenesis. Steatosis is of critical importance because prevention of fatty liver can obviate downstream pathologies of liver disease (eg, fibrosis). Recent studies have shown a strong correlation between chemical exposure and steatosis. The work described here identifies chemicals on the US Environmental Protection Agency’s Integrated Risk Information System (IRIS) that induce steatosis and investigates putative mechanisms by which these chemicals may contribute to this pathological condition. Mitochondrial impairment, insulin resistance, impaired hepatic lipid secretion, and enhanced cytokine production were identified as potential mechanisms that could contribute to steatosis. Taken together, this work is significant because it identifies multiple mechanisms by which environmental chemicals may cause fatty liver and expands our knowledge of the possible role of environmental chemical exposure in the induction and progression of liver disease.

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