Roza M et al. (2026), Juvenile exposure to imazalil disrupts epigenet...

XB-ART-61782

Sci Total Environ 2026 Mar 23;1028:181540. doi: 10.1016/j.scitotenv.2026.181540.

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Juvenile exposure to imazalil disrupts epigenetic and transcriptomic regulation of hepatic energy metabolism in Xenopus tropicalis.

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

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The extensive use of agricultural pesticides has led to widespread environmental contamination, raising concerns about their adverse biological effects. The fungicide imazalil is known to cause endocrine-disrupting and hepatotoxic effects in vertebrates, but potential underlying epigenetic mechanisms remain poorly understood. In this multiomics study, we investigated hepatic epigenetic and transcriptomic responses in juvenile Xenopus tropicalis (6.5 weeks post-metamorphosis) following two weeks exposure to an environmentally relevant concentration of imazalil (12.3 μg/L). Thousands of differentially methylated cytosines (DMCs) were identified in both sexes, whereas significant gene expression changes were primarily detected in males. The genomic locations of DMCs were largely sex-specific, with only 162 sites shared between males and females. Gene Set Enrichment Analysis indicated disruption of energy metabolism in both sexes, while sex-specific responses included downregulation of cell cycle and chromatin organization pathways in males and upregulation of immune-related pathways in females. Integration of methylation and expression data identified 8083 strong correlations involving 2303 CpGs, including individual CpG sites whose methylation levels were linked to the expression of multiple functionally related genes enriched for cell cycle regulation and chromatin organization pathways. Together, these results suggest coordinated, potentially trans-regulatory epigenetic control of hepatic transcriptional networks that may mediate imazalil-induced hepatotoxic effects. The observed sex-specific responses further suggest that disruption of sex-hormone signaling may contribute to differential sensitivity to exposure. Overall, this study highlights the toxicogenomic effects of imazalil and underscores the importance of considering epigenetic mechanisms in future chemical risk assessment frameworks, with implications for both amphibian health and human environmental exposure.

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Species referenced: Xenopus tropicalis
Genes referenced: ago2 aspm cdca8 cdk1 cenpf chaf1a chtf18 dbnl dnmt1 e2f3 espl1 fanci gins3 gtse1 h2ac21 hmgb2 kif14 mcm2 mcm3 mcm5 mtbp ncapg ncaph2 orc1 plk4 prc1.2 rad51 rad54b rrm1 spc24 sptb suv39h2 tacc3 ttk uba5 ube2c
GO keywords: cell cycle [+]

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	Graphical Abstract
	Fig. 1. Genomic distribution of differentially methylated cytosines (DMCs) in Xenopus tropicalis juveniles after exposure to imazalil (q-value <0.05). (A): Circular plots showing the distribution of DMCs across chromosomes (sectors 1–10). Cytosines were considered differentially methylated when they exhibited at least a 10% difference between treatment and control groups. (B): Pie charts showing the distribution of DMCs across genomic elements. (C): Venn diagram showing the overlap of DMCs between males and females.
	Fig. 2. Volcano plots showing gene expression differences in Xenopus tropicalis juveniles exposed to imazalil. (A) Differential gene expression in males, highlighting significantly downregulated (blue) and upregulated (red) genes. (B) Gene expression in females, where no significant DEGs were identified after FDR correction. P-values were adjusted for multiple comparisons using the Benjamini–Hochberg procedure, and genes were considered significant at adjusted p-value <0.05.
	Fig. 3. Tree plots showing the gene set enrichment analysis (GSEA) of gene expression in the liver of Xenopus tropicalis juveniles exposed to imazalil. The top 30 statistically significant enriched GO and KEGG terms (FDR < 0.05) are shown, ranked by lowest p-value. Functional grouping trees were constructed based on similarity index among enriched terms to facilitate visualization and interpretation.
	Fig. 4. (A) Network analysis of Spearman's correlations between levels of methylation in selected CpG loci and levels of downregulated genes in the liver of X. tropicalis juvenile males exposed to imazalil. Only statistically significant strong correlations are shown (FDR < 0.05, spearman's ρ > 0.8 or ρ < −0.8). Symbols of downregulated genes present in over-represented pathways are shown. Absolute spearman's ρ values shown in the figure varied between 0.833 and 0.933. (B) Gene over representation analysis of downregulated DEGs correlated with levels of methylation in selected CpG loci. BP: Biological Process; MF: Molecular Function; CC: Cellular Component; KEGG: KEGG pathway.