Genome-wide DNA methylation of the liver reveals delayed effects of
early-life exposure to 17-α-ethinylestradiol in the self-fertilizing
mangrove rivulus
Abstract
Organisms exposed to endocrine disruptors in early life can show altered
phenotype later in adulthood. Although the mechanisms underlying these
long-term effects remain poorly understood, an increasing body of
evidence points toward the potential role of epigenetic processes. In
the present study, we exposed hatchlings of an isogenic lineage of the
self-fertilizing fish mangrove rivulus for 28 days to 4 and 120 ng/L of
17-α-ethinylestradiol. After a recovery period of 140 days, reduced
representation bisulfite sequencing (RRBS) was performed on the liver in
order to assess the hepatic genome-wide methylation landscape. Across
all treatment comparisons, a total of 146 differentially methylated
fragments (DMFs) were reported, mostly for the group exposed to 4 ng/L,
suggesting a non-monotonic effect of EE2 exposure. Gene ontology
analysis revealed networks involved in lipid metabolism, cellular
processes, connective tissue function, molecular transport and
inflammation. The highest effect was reported for nipped-B-like protein
B (NIPBL) promoter region after exposure to 4 ng/L EE2 (+ 21.9%),
suggesting that NIPBL could be an important regulator for long-term
effects of EE2. Our results also suggest a significant role of DNA
methylation in intergenic regions and potentially in transposable
elements. These results support the ability of early exposure to
endocrine disruptors of inducing epigenetic alterations during
adulthood, providing plausible mechanistic explanations for long-term
phenotypic alteration. Additionally, this work demonstrates the
usefulness of isogenic lineages of the self-fertilizing mangrove rivulus
to better understand the biological significance of long-term
alterations of DNA methylation by diminishing the confounding factor of
genetic variability.