Chronic exposure of killifish to a highly polluted environment desensitizes estrogen-responsive reproductive and biomarker genes.

TitleChronic exposure of killifish to a highly polluted environment desensitizes estrogen-responsive reproductive and biomarker genes.
Publication TypeJournal Article
Year of Publication2014
AuthorsBugel, SM, Bonventre, JA, White, LA, Tanguay, RL, Cooper, KR
JournalAquat Toxicol
Volume152
Pagination222-31
Date Published2014 Jul
ISSN1879-1514
KeywordsAnimals, Biomarkers, DNA Methylation, Estrogens, Female, Fundulidae, Gene Expression Regulation, Male, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Reproduction, Signal Transduction, Vitellogenins, Water Pollutants, Chemical
Abstract

Reproductive and endocrine disruption is commonly reported in aquatic species exposed to complex contaminant mixtures. We previously reported that Atlantic killifish (Fundulus heteroclitus) from the chronically contaminated Newark Bay, NJ, exhibit multiple endocrine disrupting effects, including inhibition of vitellogenesis (yolk protein synthesis) in females and false negative vitellogenin biomarker responses in males. Here, we characterized the effects on estrogen signaling and the transcriptional regulation of estrogen-responsive genes in this model population. First, a dose-response study tested the hypothesis that reproductive biomarkers (vtg1, vtg2, chg H, chg Hm, chg L) in Newark Bay killifish are relatively less sensitive to 17β-estradiol at the transcriptional level, relative to a reference (Tuckerton, NJ) population. The second study assessed expression for various metabolism (cyp1a, cyp3a30, mdr) and estrogen receptor (ER α, ER βa, ER βb) genes under basal and estrogen treatment conditions in both populations. Hepatic metabolism of 17β-estradiol was also evaluated in vitro as an integrated endpoint for adverse effects on metabolism. In the third study, gene methylation was evaluated for promoters of vtg1 (8 CpGs) and vtg2 (10 CpGs) in both populations, and vtg1 promoter sequences were examined for single nucleotide polymorphism (SNPs). Overall, these studies show that multi-chemical exposures at Newark Bay have desensitized all reproductive biomarkers tested to estrogen. For example, at 10ng/g 17β-estradiol, inhibition of gene induction ranged from 62% to 97% for all genes tested in the Newark Bay population, relative to induction levels in the reference population. The basis for this recalcitrant phenotype could not be explained by a change in 17β-estradiol metabolism, nuclear estrogen receptor expression, promoter methylation (gene silencing) or SNPs, all of which were unaltered and normal in the Newark Bay population. The decreased transcriptional sensitivity of estrogen-responsive genes is suggestive of a broad effect on estrogen receptor pathway signaling, and provides insight into the mechanisms of the endocrine disrupting effects in the Newark Bay population.

DOI10.1016/j.aquatox.2014.04.014
Alternate JournalAquat. Toxicol.
PubMed ID24794048
PubMed Central IDPMC4084733
Grant ListES007060 / ES / NIEHS NIH HHS / United States
ES05022 / ES / NIEHS NIH HHS / United States
P30 ES005022 / ES / NIEHS NIH HHS / United States
P42 ES016465 / ES / NIEHS NIH HHS / United States
T32 ES007060 / ES / NIEHS NIH HHS / United States
P30 ES000210 / ES / NIEHS NIH HHS / United States