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Aquat Toxicol. 2017 Dec;193:18-29. doi: 10.1016/j.aquatox.2017.09.025. Epub 2017 Sep 28.

Paternal exposure to environmental 17-alpha-ethinylestradiol concentrations modifies testicular transcription, affecting the sperm transcript content and the offspring performance in zebrafish.

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Department of Molecular Biology, Universidad de León, 24071, León, Spain; INDEGSAL, Universidad de León, 24071, León, Spain.
INDEGSAL, Universidad de León, 24071, León, Spain; IEO, Spanish Institute of Oceanography, Planta de Cultivos el Bocal, Barrio Corbanera s/n, Monte, Santander, 39012, Spain.
Department of Molecular Biology, Universidad de León, 24071, León, Spain; INDEGSAL, Universidad de León, 24071, León, Spain. Electronic address:


The synthetic estrogen 17-α-ethinylestradiol (EE2), a major constituent in contraceptive pills, is an endocrine disrupting chemical (EDC) present in the aquatic environment at concentrations of ng/L. Developmental exposure to these low concentrations in fish can induce several disorders. Zebrafish (Danio rerio) is a perfect organism for monitoring the effects of environmental contaminants. Our hypothesis is that changes promoted by EE2 in the germ line of male adults could be transmitted to the unexposed progeny. We exposed male zebrafish to 2.5, 5 and 10ng/L of EE2 during spermatogenesis and mated them with untreated females. Detailed progeny development was studied concentrating to survival, hatching and malformations. Due to the high incidence of lymphedemas within larvae, we performed qPCR analysis of genes involved in lymphatic development (vegfc and vegfr3) and endothelial cell migration guidance (cxcr4a and cxcl12b). Estrogen receptor (ER) transcript presence was also evaluated in sperm, testis and embryos. Progenies showed a range of disorders although at a low incidence: skeletal distortions, uninflated swimbladder, lymphedema formation, cartilage deformities and otolith tethering. Swimming evaluation revealed less active locomotion. All these processes are related to pathways involving ERs (esr1, esr2a and esr2b). mRNA analysis revealed that environmental EE2 causes the up-regulation of esr1 an esr2b in testis and the increase of esr2b transcripts in sperm pointing to a link between lymphedema in embryos and ER expression impairment. We demonstrate that the effects induced by environmental toxicants can be paternally inherited and point to the changes on the sperm transcriptome as the responsible mechanism.


17-α-ethinylestradiol; Endocrine disruption; Lymphedema; Sperm mRNAs; Transgenerational inheritance; Zebrafish

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