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Transcriptional profiling efficacy to define biological activity similarity for cosmetic ingredients’ safety assessment based on next generation read-across

ABSTRACT: The objective of this work was to use transcriptional profiling to assess the biological activity of structurally related chemicals to define their biological similarity and with that, substantiate the validity of a read-across approach usable in risk assessment. Two case studies are presented, one with 4 short alkyl chain parabens: methyl (MP), ethyl (EP), butyl (BP), and propyl paraben (PP), as well as their main metabolite, p-Hydroxybenzoic acid (pHBA) with the assumption that PP was the target chemical; and a second one with caffeine (CA) and its main metabolites theophylline (TP), theobromine (TB) and paraxanthine (PX), where caffeine was the target chemical. The comprehensive transcriptional response of MCF7, HepG2, A549 and ICell cardyomiocytes was evaluated (TempO-Seq) after exposure to vehicle-control, each paraben or pHBA, caffeine or its metabolites, at 3 non-cytotoxic concentrations, for 6h. Differentially expressed genes (FDR ≥ 0.05, and fold change ±1.2≥) were identified for each chemical, at each dose of exposure, and used to determine similarities between them. Each of the chemicals is able to elicit changes in the expression of a number of genes, as compared to controls, particularly at the highest dose tested. Importantly, the transcriptional profile elicited by each of the parabens shares a high degree of similarities across the category members. The highest number of genes commonly affected by the parabens was found between BP and PP. The transcriptional profile of the parabens is similar to the one elicited by some estrogen receptor agonist, among other actives. Pathway enrichment analysis (MSigDB v7.0) of the transcriptional profile for each paraben indicated a significant overlap in the up- and down-regulated pathways across the four parabens.The highest similarity in biological activity was found between BP and PP. This was indicative of their biological similarity, and thus the validity of the read across among the group, with BT being the closest structural and biological analogue for PP. In the caffeine case and its main metabolites, the transcriptional profile elicited of all four compounds had a high degree of similarity across the cell types, with CA and TP being the most active. The most robust response was obtained in the cardiomyocytes with the highest transcriptional profile similarity between CA and TP. The transcriptional profile of the methylxantines is similar to the one elicited by inhibitors of phosphatidylinositol 3-kinase as well as other actives. Pathway enrichment analysis (MSigDB v7.0) of the transcriptional profile for each compound indicated a significant overlap in the up- and down-regulated pathways across the four methylxanthines. The highest similarity in biological activity was found between CA and TP, supporting the conclusion that from the group of methylxantines evaluated TP is the most appropriate analogue to read-across for CA. Overall, our results support the approach of incorporating transcriptional profiling in well-designed in vitro tests to support biological similarity driven read-across procedures and strengthening the traditional structure-based approaches useful in risk assessment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE218902 | GEO | 2023/01/11

REPOSITORIES: GEO

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Project description:Background: Responses to hypoxia have been investigated in many species; however, comparative study between conspecific geographical populations in different altitude regions is rare, especially for invertebrates . The migratory locust, Locusta migratoria, is widely distributed both on high-altitude Tibetan Plateau (TP) and on low-altitude North China Plain (NP). TP locusts have inhabited Tibetan Plateau since Quaternary glaciations events and thus probably have evolved superior capacity to deal with hypoxia. Results: Here we compared the hypoxic responses of TP and NP locusts from morphological, behavioral and physiological perspectives. We found that TP locusts were more tolerant of extreme hypoxia than NP locusts, with a lower proportion exhibiting stupor, a faster recovery time, and higher respiration rates. We compared the transcriptional profiles of field TP and NP locusts and found that their differences were possibly attributed to a combination of multiple factors, e.g. oxygen, UV radiation, temperature and nutrition. To evaluate why TP locusts respond to extreme hypoxia differently from NP locusts, we subjected them to extreme hypoxia and compared their transcriptional responses. We found that the aerobic metabolism was more active in TP locusts than in NP locusts. RNAi disruption of PDHE1b, an entry gene from glycolysis to TCA cycle, increased the ratio of stupor in Tibetan locusts and decreased the ATP content of Tibetan locusts in hypoxia, confirming the significant importance of this metabolic branch for TP locusts to conquer hypoxia. Conclusions: Here we show that TP locusts are better tolerant of hypoxia than NP locusts and the better capacity to modulate primary metabolism in TP locusts contributes to their superior tolerance of hypoxia compared to NP locusts. FIELD POPULATION: TP locusts vs. NP locusts;direct comparison on 6 separate microarrays; each microarray compares one biological replicate; each biological replicate contains 10 individuals. LAB POPULATION: hypoxia-treated TP locusts vs TP locusts in normoxia; hypoxia-treated NP locusts vs NP locusts in normoxia; direct comparison on 6 separate microarrays; each microarray compares one biological replicate; each biological replicate contains 10 individuals.

Project description:Our previous research demonstrated that caffeine exposure on embryonic day (E) 8.5 increased body weight, altered cardiac morphology and function in adult male mice. However, these adverse effects were not observed in adenosine A1 receptor knockout (A1AR-/-) mice. Our hypothesis is that A1AR action mediates changes in DNA methylation patterns in mice exposed in utero to caffeine and that these changes in methylation lead to long-term effects in adult mice. To test this hypothesis, DNA Methylation 2.1M Deluxe Promoter Arrays (NimbleGen) were used to examine the methylation patterns of DNA isolated from adult left ventricles of the A1AR knockout line exposed to 20 mg/kg caffeine at E8.5 in utero. In A1AR+/+ mice, 4,896 hypermethylated and 2,823 hypomethylated regions were discovered in the left ventricles of the caffeine group compared to the normal saline group. In A1AR-/- mice, 1,024 hypermethylated and 1,757 hypomethylated regions were found in the caffeine group. The differentially methylated regions (DMRs) in the caffeine treated A1AR+/+ hearts mapped to 6,148 genes, 4,853 promoters, 4,111 primary transcripts, 816 CpG islands, and 98 miRNAs. Functional annotation clustering of genes revealed that many genes were involved in the development of hypertrophic cardiomyopathy and other heart diseases, which may explain our earlier findings of thickening of the left ventricular wall after in utero caffeine treatment. The methylation changes in several DMRs, mef2c, ins2, tnnt2, and myh6, were validated by bisulfite sequencing. In summary, in utero caffeine exposure caused DNA methylation changes in adult left ventricles and that these changes may be mediated by A1ARs. Pregnant mice were injected at embryonic day 8.5 with 0.9% NaCl (vehicle) or 20 mg/kg caffeine in vehicle i.p. Pups were born and raised until 8-10 weeks of age. Analysis was performed on the following groups vehicle A1AR+/+ (veh+/+), vehicle A1AR-/- (veh-/-), caffeine A1AR+/+ (caff+/+), and caffeine A1AR-/- (caff-/-). Genomic DNA from left ventricles of adult male mice was used. Two biological replicates were measured for each group.

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Transcriptional profiling efficacy to define biological activity similarity for cosmetic ingredients’ safety assessment based on next generation read-across

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