Abstract
Glufosinate-ammonium (GLA) is a widely used herbicide with emerging concern over its male reproductive toxicity. Abnormalities in sperm histone modification induced by GLA exposure observed in our previous study aroused our interest in whether such alterations could further affect embryonic gene expression. Here we administered adult male mice with 0.2 mg/kg⋅day of GLA for 5 weeks to collect their sperm or 4-cell embryos after copulation. Cleavage Under Targets and Tagmentation (CUT&Tag) sequencing showed alterations of sperm H3 lysine 4 trimethylation (H3K4me3) and histone H3 lysine 27 acetylation (H3K27ac), which are active histone modification marks involved in embryo development, while RNA sequencing identified differentially expressed genes in 4-cell embryos. Differentially H3K4me3 and H3K27ac occupied regions were mainly distributed at the gene promoters and putative enhancers, and were enriched in pathways related to the immune system and nervous system. Integrative analysis of these sequencing data showed that genes such as Mgl2 with increased H3K4me3 and H3K27ac in sperm were up-regulated in embryos, and vice versa for genes such as Dcn. Additionally, differentially occupied H3K4me3 and H3K27ac in sperm were linked to gene expression changes in both paternal and maternal alleles of 4-cell embryos. In conclusion, GLA-induced changes in sperm H3K4me3 and H3K27ac are concordant with gene expression in preimplantation embryos, which might further affect embryo development and offspring health.
Highlights
Histones consisting of H2A, H2B, H3, and H4 are proteins that are critical in the packing of DNA into the cell
We investigated genome-wide H3K4me3 and H3K27ac in sperm and transcriptome in preimplantation embryos to identify the potential hazard of GLA exposure, and integrated these sequencing data to find some clues on their association
Our study revealed that GLA exposure altered H3K4me3 and H3K27ac profiles in mouse sperm, which was linked to aberrant gene expression in preimplantation embryos
Summary
Histones consisting of H2A, H2B, H3, and H4 are proteins that are critical in the packing of DNA into the cell. The retained histones in sperm bearing abundant modifications are still essential in male reproduction (Liu et al, 2019), embryo development (Hammoud et al, 2009; Yoshida et al, 2018) and offspring health (Siklenka et al, 2015). Sperm H3K27ac is highly associated with in vivo fertility (Kutchy et al, 2018) and 3D chromatin architecture in embryos (Wike et al, 2021). Both sperm H3K4me and H3K27ac are essential for fertility and embryo development
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