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Differentially expressed genes by DMSO in mouse 2-cell embryos identified by RNA sequencing

ABSTRACT: Since discovery of dimethyl sulfoxide (DMSO), it has been applied to the multidisciplinary studies for basic and clinic research; yet its toxicity versus biocompatibility is poorly understood, leading to our inability to discover etiology behind its paradox. Here, we found that exposure of 2% DMSO to mouse zygotes caused developmental arrest at 2/4-cell embryos, and showed a decreased total acetylation levels. Besides, H3, H4, p53, H3K9, and H3K27 acetylation levels at DMSO-exposed 2-cell embryos are significantly increased. This affected the male pronucleus more than female. Further, RNA-sequence data demonstrates that DMSO alters approximately 16.26% transcripts of 2-cell embryos. Among them, maternal and minor zygotic gene activation (ZGA) transcripts are highly increased, whereas ubiquitin-proteasome system, major ZGA, embryonic gene activation, cell cycle, and ribosomal biogenesis transcripts are significantly down-regulated. These results suggest that DMSO caused developmental arrest by disrupting maternal-to-embryonic transition due to low proteasome activity and epigenetic alternations.

ORGANISM(S): Mus musculus

PROVIDER: GSE124598 | GEO | 2019/11/08

REPOSITORIES: GEO

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Project description:3,3’,5.5’-Tetrabromobisphenol A (TBBPA) is a widely used brominated flame-retardant utilized in the production of electronic devices and plastic paints. The objective of this study is to use zebrafish as a model and determine the effects of TBBPA exposure on early embryogenesis. We initiated TBBPA exposures (0, 10, 20 and 40μM) at 0.75 h post fertilization (hpf) and monitored early developmental events such as cleavage, blastula and epiboly that encompass maternal-to-zygotic transition (MZT) and zygotic genome activation (ZGA). Our data revealed that TBBPA exposures induced onset of developmental delays by 3 hpf (blastula). By 5.5 hpf (epiboly), TBBPA-exposed (10-20 μM) embryos showed concentration-dependent developmental lag by up to 3 stages or 100% mortality at 40 μM. Interestingly, while continued 0.75- 48 hpf TBBPA exposures (10 μM) led to severely deformed embryos, replacing exposure solution with chemical-free media at 6 hpf mitigated this effect, with 100% normal embryos at 48 hpf. To examine the genetic basis of TBBPA-induced delays, we conducted mRNA-sequencing on embryos exposed to 0 or 40 μM TBBPA from 0.75 hpf to 2, 3.5 or 4.5 hpf. Read count data showed that while TBBPA exposures had no overall impacts on maternal or maternal-zygotic genes, collective read counts for zygotically activated genes were lower in TBBPA treatment at 4.5 hpf compared to time-matched controls, suggesting that TBBPA delays ZGA. Gene ontology assessments for both time- and stage-matched differentially expressed genes revealed TBBPA-induced inhibition of chromatin assembly- a process regulated by histone modifications. Since acetylation is the primary histone modification system operant during early ZGA, we hypothesized that TBBPA inhibits histone acetylation, resulting in lack of open chromatin within promoters of zygotic genes and delaying ZGA. Therefore, we co-exposed embryos to 20 μM TBBPA and 100 μM N-(4-Chloro-3-(trifluoromethyl)phenyl)-2-ethoxybenzamide (CTB) -a histone acetyltransferase activator that promotes histone acetylation- and showed that TBBPA-CTB co-exposures from 0.75- 3 hpf significantly reversed TBBPA-only developmental delays, suggesting that TBBPA-induced phenotypes are indeed driven by repression of histone acetylation. Collectively, our work demonstrates that TBBPA disrupts ZGA and early developmental morphology, potentially by inhibiting histone acetylation. Future studies will focus on mechanisms of TBBPA-induced chromatin modifications.

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Differentially expressed genes by DMSO in mouse 2-cell embryos identified by RNA sequencing

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