Roza M et al. (2024), Male-transmitted transgenerational effects of t...

XB-ART-60588

Sci Total Environ 2024 May 01;923:170949. doi: 10.1016/j.scitotenv.2024.170949.

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Male-transmitted transgenerational effects of the herbicide linuron on DNA methylation profiles in Xenopus tropicalis brain and testis.

Roza M , Eriksson ANM , Svanholm S , Berg C , Karlsson O .

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The herbicide linuron can cause endocrine disrupting effects in Xenopus tropicalis frogs, including offspring that were never exposed to the contaminant. The mechanisms by which these effects are transmitted across generations need to be further investigated. Here, we examined transgenerational alterations of brain and testis DNA methylation profiles paternally inherited from grandfathers developmentally exposed to an environmentally relevant concentration of linuron. Reduced representation bisulfite sequencing (RRBS) revealed numerous differentially methylated regions (DMRs) in brain (3060 DMRs) and testis (2551 DMRs) of the adult male F2 generation. Key genes in the brain involved in somatotropic (igfbp4) and thyrotropic signaling (dio1 and tg) were differentially methylated and correlated with phenotypical alterations in body size, weight, hind limb length and plasma glucose levels, indicating that these methylation changes could be potential mediators of the transgenerational effects of linuron. Testis DMRs were found in genes essential for spermatogenesis, meiosis and germ cell development (piwil1, spo11 and tdrd9) and their methylation levels were correlated with the number of germ cells nests per seminiferous tubule, an endpoint of disrupted spermatogenesis. DMRs were also identified in several genes central for the machinery that regulates the epigenetic landscape including DNA methylation (dnmt3a and mbd2) and histone acetylation (hdac8, ep300, elp3, kat5 and kat14), which may at least partly drive the linuron-induced transgenerational effects. The results from this genome-wide DNA methylation profiling contribute to better understanding of potential transgenerational epigenetic inheritance mechanisms in amphibians.

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Species referenced: Xenopus tropicalis
Genes referenced: brip1 ddx4 dio1 dnmt3a elp3 ep300 esrrg gabbr1 gabbr2 gabrb3 grik2 grin1 grin2b grm1 grm4 grm5 hdac8 hsd17b12 iftap igfbp4 igfbp5 irs2 kat14 kat5 kiss2 lhcgr mael mbd2 mre11 pgrmc2 piwil1 prkag2 prkar1b slc17a7 spo11 syt6 tdrd9 tg top2a trhde trhr3
GO keywords: brain development [+]

Phenotypes: Xtr wt F0 + linuron (herbicide) (Table 3.) [+]

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	Graphical Abstract
	Fig. 1. (A) Volcano plots showing differentially methylated regions (DMRs) in the brain (3060 DMRs: 1574 hypermethylated, 1486 hypomethylated)) and testis (2551 DMRs: 1445 hypermethylated, 1106 hypomethylated)) of adult Xenopus tropicalis F2 males after grand-paternal developmental exposure to linuron. Genomic regions (100 bp) were considered differentially methylated if they had at least 10 % methylation difference between control and treatment and q-value < 0.05 (N.S. = non-significant). (B) Pie charts showing the percentage of DMRs located in promoter, gene body (introns and exons) and intergenic regions.
	Fig. 2. Gene Ontology (GO) terms with over-represented gene sets related to DMRs in the brain and testis of adult Xenopus tropicalis F2 males after grand-paternal developmental exposure to linuron. In the brain, no gene sets were significantly over-represented after false discovery rate (FDR) correction, therefore, unadjusted p-values are presented in the legend. In the testis, gene sets related with five GO terms were over-represented, and FDR adjusted p-values are presented.
	Fig. 3. KEGG pathways with over-represented gene sets related to DMRs in the brain of adult Xenopus tropicalis F2 males after grand-paternal developmental exposure to linuron. In the testis, no KEGG pathways were significantly over-represented after false discovery rate (FDR) correction.
	Table 3. Phenotype measurements in adult Xenopus tropicalis F2 males after grand-paternal developmental exposure to linuron. Asterisks indicate statistically significant difference between control and Linuron F2 groups. (Mann-Whitney U test, * p < 0.05, ** p < 0.01).