Cross-species toxicogenomic analyses and phenotypic anchoring in response to groundwater low-level pollution

Porreca, Immacolata; D’Angelo, Fulvio; Gentilcore, Daniela; Carchia, Emanuele; Amoresano, Angela; Affuso, Andrea; Ceccarelli, Michele; Luca, Pasquale De; Esposito, Libera; Guadagno, Francesco M.; Mallardo, Massimo; Nardone, Antonio; Maccarone, Sergio; Pane, F.; Scarfò, Marzia; Sordino, Paolo; Felice, Mario De; Ambrosino, Concetta

doi:10.1186/1471-2164-15-1067

Cited by 8 publications

(6 citation statements)

References 69 publications

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“…Moving from our experience143233, we planned an in vitro toxicogenomics experiment, in differentiated cells (immortalized thyrocytes), to identify gene signatures, mechanisms of toxicity or/and adverse outcomes potentially active in vivo of two pesticides, ETU and CPF. They were chosen for their known effects on thyroid physiology1011, up to now not characterized at the level of thyroid gene expression.…”

Section: Discussionmentioning

confidence: 99%

Pesticide toxicogenomics across scales: in vitro transcriptome predicts mechanisms and outcomes of exposure in vivo

Porreca

D’Angelo

Franceschi

et al. 2016

Sci Rep

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In vitro Omics analysis (i.e. transcriptome) is suggested to predict in vivo toxicity and adverse effects in humans, although the causal link between high-throughput data and effects in vivo is not easily established. Indeed, the chemical-organism interaction can involve processes, such as adaptation, not established in cell cultures. Starting from this consideration we investigate the transcriptomic response of immortalized thyrocytes to ethylenthiourea and chlorpyrifos. In vitro data revealed specific and common genes/mechanisms of toxicity, controlling the proliferation/survival of the thyrocytes and unrelated hematopoietic cell lineages. These results were phenotypically confirmed in vivo by the reduction of circulating T4 hormone and the development of pancytopenia after long exposure. Our data imply that in vitro toxicogenomics is a powerful tool in predicting adverse effects in vivo, experimentally confirming the vision described as Tox21c (Toxicity Testing in the 21st century) although not fully recapitulating the biocomplexity of a living animal.

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Section: Discussionmentioning

confidence: 99%

Pesticide toxicogenomics across scales: in vitro transcriptome predicts mechanisms and outcomes of exposure in vivo

Porreca

D’Angelo

Franceschi

et al. 2016

Sci Rep

Self Cite

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“…Microarrays were performed with the Affymetrix platform using GeneChip ® Rat Gene 2.0 ST Arrays (Affymetrix). Gene expression profiling experiments and data analyses were conducted as described [ 22 ]. Briefly, all samples passed the quality control check and the reproducibility of replicates was assessed by PCA.…”

Section: Methodsmentioning

confidence: 99%

“Stockpile” of Slight Transcriptomic Changes Determines the Indirect Genotoxicity of Low-Dose BPA in Thyroid Cells

et al. 2016

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Epidemiological and experimental data highlighted the thyroid-disrupting activity of bisphenol A (BPA). Although pivotal to identify the mechanisms of toxicity, direct low-dose BPA effects on thyrocytes have not been assessed. Here, we report the results of microarray experiments revealing that the transcriptome reacts dynamically to low-dose BPA exposure, adapting the changes in gene expression to the exposure duration. The response involves many genes, enriching specific pathways and biological functions mainly cell death/proliferation or DNA repair. Their expression is only slightly altered but, since they enrich specific pathways, this results in major effects as shown here for transcripts involved in the DNA repair pathway. Indeed, even though no phenotypic changes are induced by the treatment, we show that the exposure to BPA impairs the cell response to further stressors. We experimentally verify that prolonged exposure to low doses of BPA results in a delayed response to UV-C-induced DNA damage, due to impairment of p21-Tp53 axis, with the BPA-treated cells more prone to cell death and DNA damage accumulation. The present findings shed light on a possible mechanism by which BPA, not able to directly cause genetic damage at environmental dose, may exert an indirect genotoxic activity.

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“…Gene expression profiling experiments and data analyses were conducted as elsewhere described. 59 The Affimetrix platform was used. cRNA was generated by using the Affymetrix One-Cycle Target Labeling and Control Reagent kit (Affymetrix Inc., Foster City, CA, USA), according to the manufacturer's instructions, starting from 5 μ g of total RNA.…”

Section: Methodsmentioning

confidence: 99%

Evaluation of low doses BPA-induced perturbation of glycemia by toxicogenomics points to a primary role of pancreatic islets and to the mechanism of toxicity

et al. 2015

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Epidemiologic and experimental studies have associated changes of blood glucose homeostasis to Bisphenol A (BPA) exposure. We took a toxicogenomic approach to investigate the mechanisms of low-dose (1 × 10−9 M) BPA toxicity in ex vivo cultures of primary murine pancreatic islets and hepatocytes. Twenty-nine inhibited genes were identified in islets and none in exposed hepatocytes. Although their expression was slightly altered, their impaired cellular level, as a whole, resulted in specific phenotypic changes. Damage of mitochondrial function and metabolism, as predicted by bioinformatics analyses, was observed: BPA exposure led to a time-dependent decrease in mitochondrial membrane potential, to an increase of ROS cellular levels and, finally, to an induction of apoptosis, attributable to the bigger Bax/Bcl-2 ratio owing to activation of NF-κB pathway. Our data suggest a multifactorial mechanism for BPA toxicity in pancreatic islets with emphasis to mitochondria dysfunction and NF-κB activation. Finally, we assessed in vitro the viability of BPA-treated islets in stressing condition, as exposure to high glucose, evidencing a reduced ability of the exposed islets to respond to further damages. The result was confirmed in vivo evaluating the reduction of glycemia in hyperglycemic mice transplanted with control and BPA-treated pancreatic islets. The reported findings identify the pancreatic islet as the main target of BPA toxicity in impairing the glycemia. They suggest that the BPA exposure can weaken the response of the pancreatic islets to damages. The last observation could represent a broader concept whose consideration should lead to the development of experimental plans better reproducing the multiple exposure conditions.

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Cross-species toxicogenomic analyses and phenotypic anchoring in response to groundwater low-level pollution

Cited by 8 publications

References 69 publications

Pesticide toxicogenomics across scales: in vitro transcriptome predicts mechanisms and outcomes of exposure in vivo

Pesticide toxicogenomics across scales: in vitro transcriptome predicts mechanisms and outcomes of exposure in vivo

“Stockpile” of Slight Transcriptomic Changes Determines the Indirect Genotoxicity of Low-Dose BPA in Thyroid Cells

Evaluation of low doses BPA-induced perturbation of glycemia by toxicogenomics points to a primary role of pancreatic islets and to the mechanism of toxicity

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