Endocrine disruptors cause multigenerational and transgenerational epigenetic changes in fish exposed during early life

Kaley Major1, Bethany Michele DeCourten2, Joshua Forbes3, Alvina Mehinto4, Jie Li5, Matt Settles5, Richard Connon6 and Susanne M Brander7, (1)Oregon State University, Department of Environmental and Molecular Toxicology, Corvallis, OR, United States, (2)University of North Carolina at Wilmington, Wilmington, NC, United States, (3)University of North Carolina at Wilmington, United States, (4)Southern California Coastal Water Research Project, United States, (5)University of California Davis, United States, (6)University of California, Davis, Veterinary Medicine: Anatomy, Physiology & Cell Biology, Davis, CA, United States, (7)Oregon State University, Department of Environmental and Molecular Toxicology, Corvallis, United States
Abstract:
The inland silverside, Menidia beryllina, is a euryhaline fish native to the Eastern United States and a model organism in ecotoxicology. We previously showed that low-level exposure to endocrine disrupting chemicals (EDCs) can cause a variety of effects in M. beryllina, from changes in gene expression to morphological deformities. In the present study, we explore the potential for early life exposure to EDCs to cause epigenetic changes in inland silversides, with a particular focus on transgenerational effects. EDCs included contaminants of emerging concern (the pyrethroid insecticide bifenthrin and the synthetic progestin levonorgestrel), as well as an estrogen (17-β ethinylestradiol), and an androgen (trenbolone) at exposure levels between 3 and 9 ng/L. In a multigenerational experiment, we exposed parental silversides to EDCs from fertilization until 21 days post hatch (dph). We assessed DNA methylation patterns for three generations (P0, F1, and F2) in whole body larval fish using reduced representation bisulfite sequencing (RRBS). We found significant (p < 0.05) differences in promoter and/or gene body methylation in treatment fish relative to controls for all EDCs. A select subset of genes that have been previously associated with endocrine disruption showed differential methylation across all treatments. Using GO enrichment and KEGG pathway enrichment analyses, we found that differentially methylated genes in EDC treatments included hormone receptors, genes involved in steroidogenesis, prostaglandin synthesis, sexual development, DNA methylation, protein metabolism and synthesis, cell signaling, and neurodevelopment. Differential gene methylation relative to control was often present in the F1 generation, exposed as primordial germ cells within larval parents, and sometimes noted into the F2 generation, which was unexposed to EDCs. These findings show that EDCs can cause altered methylation in genes that are functionally relevant to impaired phenotypes documented in EDC-exposed animals, and that EDC exposure has the potential to have effects on subsequent generations of unexposed fish.
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