Sex-specific intergenerational epigenetic responses to real-world chemical mixture exposure in an outbred sheep model
- 1Schools of Biosciences and Veterinary Medicine and Science, University of Nottingham , Sutton Bonington, LE12 5RD ,
- 2Department of Pediatrics, University of Michigan , Ann Arbor, MI ,
- 3School of Biodiversity One Health and Veterinary Medicine, University of Glasgow ,
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.
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BibTeX
@article{hargreaves2026sexspecific,
title = {{Sex-specific intergenerational epigenetic responses to real-world chemical mixture exposure in an outbred sheep model}},
author = {Oliver G Hargreaves and Wing Yee Kwong and Andrew Warry and Desmond AR Tutt and Vasantha Padmanabhan and Neil P Evans and Richard G Lea and Michelle Bellingham and Kevin D Sinclair},
journal = {PNAS Nexus},
year = {2026},
month = oct,
doi = {10.1093/pnasnexus/pgag338},
url = {https://academic.oup.com/pnasnexus/advance-article/doi/10.1093/pnasnexus/pgag338/8907316},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Sex-specific intergenerational epigenetic responses to real-world chemical mixture exposure in an outbred sheep model
AU - Oliver G Hargreaves
AU - Wing Yee Kwong
AU - Andrew Warry
AU - Desmond AR Tutt
AU - Vasantha Padmanabhan
AU - Neil P Evans
AU - Richard G Lea
AU - Michelle Bellingham
AU - Kevin D Sinclair
PY - 2026
DA - 2026/10/10
JO - PNAS Nexus
DO - 10.1093/pnasnexus/pgag338
UR - https://academic.oup.com/pnasnexus/advance-article/doi/10.1093/pnasnexus/pgag338/8907316
AB - 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.
SN - 2752-6542
ER -