PUBLICATION
Adaptive significance of ERα splice variants in killifish (Fundulus heteroclitus) resident in an estrogenic environment
- Authors
- Cott, K.A., Nacci, D., Champlin, D., Yeo, A.T., Gilmore, T.D., Callard, G.V.
- ID
- ZDB-PUB-160414-7
- Date
- 2016
- Source
- Endocrinology 157(6): 2294-308 (Journal)
- Registered Authors
- Callard, Gloria V.
- Keywords
- none
- MeSH Terms
-
- Alternative Splicing/genetics*
- Animals
- Embryo, Nonmammalian/drug effects
- Embryo, Nonmammalian/metabolism
- Estrogen Receptor alpha/genetics*
- Estrogens/toxicity*
- Fundulidae
- Polymerase Chain Reaction
- RNA Splicing/genetics
- Water Pollutants, Chemical/toxicity
- Zebrafish
- PubMed
- 27070100 Full text @ Endocrinology
Citation
Cott, K.A., Nacci, D., Champlin, D., Yeo, A.T., Gilmore, T.D., Callard, G.V. (2016) Adaptive significance of ERα splice variants in killifish (Fundulus heteroclitus) resident in an estrogenic environment. Endocrinology. 157(6):2294-308.
Abstract
The possibility that chronic, multigenerational exposure to environmental estrogens selects for adaptive hormone response phenotypes is a critical unanswered question. Embryos/larvae of killifish from an estrogenic polluted environment (New Bedford Harbor, NBH), as compared to those from a reference site, overexpress estrogen receptor α (ERα) mRNA but are hypo-responsive to estradiol (E2). Analysis of ERα mRNAs in the two populations revealed differences in splicing of the gene encoding ERα (esr1). Here we tested the transactivation functions of four differentially expressed ERα mRNAs and tracked their association with the hypo-responsive phenotype for three generations after transfer of NBH parents to a clean environment. Deletion variants ERαΔ6 and ERαΔ6-8 were specific to NBH killifish; had dominant negative functions in an in vitro reporter assay; and were heritable. Morpholino-mediated induction of ERαΔ6 mRNA in zebrafish embryos verified its role as a dominant negative ER on natural estrogen-responsive promoters. Alternate long (ERαL) and short (ERαS) 5'-variants were similar transcriptionally but differed in estrogen responsiveness (ERαS ≫ ERαL). ERαS accounted for high total ERα expression in F1 NBH embryos/larvae but this trait was abolished by transfer to clean water. By contrast, the hypo-responsive phenotype of F1 NBH embryos/larvae persisted after long term lab holding but reverted to a normal or hyper-responsive phenotype after two or three generations, suggesting the acquisition of physiological or biochemical traits that compensate for ongoing expression of negative-acting ERαΔ6 and ERαΔ6-8 isoforms. We conclude that a heritable change in the pattern of alternative splicing of ERα pre-mRNA is part of a genetic adaptive response to estrogens in a polluted environment.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping