Sex-specific intergenerational epigenetic responses to real-world chemical mixture exposure in an outbred sheep model

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ID: 332012
2026
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Abstract
Abstract Establishing whether real-world environmental chemical (EC) exposure can induce heritable epigenetic modifications in large, outbred mammals is key to determining long-term developmental impacts of the human exposome. Using an established biosolids-treated pasture (BS) sheep model, we investigated whether gestational exposure to low-level mixtures of EC induced heritable changes in DNA methylation across three generations of sheep. Reduced-representation bisulfite sequencing of liver, blood, and sperm, combined with a structured, lineage-controlled breeding design, revealed widespread but lineage- and sex-specific differentially methylated loci (DML) in F1 offspring, with detectable alterations evident in F2 and F3 descendants. Although most DML were unique to individual sire lineages, or to a single generation, subsets of loci showed repeated involvement across generations and were associated with altered gene expression in F3 descendants. Sperm from F1 males exhibited reduced methylation at numerous loci and, together with seminal plasma, revealed differential expression of several microRNAs. These effects, however, showed limited persistence in F2 males, indicative of intergenerational rather than fully transgenerational persistence. Collectively, these findings demonstrate that complex, low-level chemical exposures can elicit recurrent, sexually dimorphic epigenetic responses in outbred species, but underscore the challenge of disentangling exposure-induced inheritance from genetically regulated methylation variation.
Reference Key
openalex_W7221339533 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Oliver George Hargreaves, Wing Yee Kwong, Andrew Warry, Desmond A. R. Tutt, Vasantha Padmanabhan, Neil P. Evans, Richard G. Lea, Michelle Bellingham, Kevin D. Sinclair
Journal PNAS nexus
Year 2026
DOI
10.1093/pnasnexus/pgag338
URL
https://doi.org/10.1093/pnasnexus/pgag338
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