Hypoxia disrupts gene modulation along the brain-pituitary-gonad (BPG)-liver axis

Hypoxia alters sex hormone concentrations leading to reproductive impairment in fish; however the mechanisms underlying these effects remain largely unknown. Using zebrafish (Danio rerio), this study is the first to demonstrate that hypoxia causes endocrine disruption by simultaneously acting on multiple targets along the brain-pituitary-gonadal (BPG)-liver axis in fish. Alterations in the expression of key genes associated with reproductive endocrine pathways in the brain (sGnRH), pituitary (FSHβ and LHβ), gonads (FSH-R, LH-R, HMGR, StAR, CYP19A, CYP11A, CYP11β and 20β-HSD), and liver were correlated with significant reductions of estradiol in females and testosterone in males. Hypoxia also induced sex-specific and tissue-specific changes in the expression of estrogen, androgen, and membrane progestin receptors along the BPG axis, suggesting disruption of the feedback and synchronization of hormone signals. Furthermore, the hypoxia-induced upregulation of hepatic sex hormone-binding globulin suggests an increase in hormone transport and reduced bioavailability in blood, while upregulation of hepatic CYP3A65 and CYP1A in females suggests an increase in estrogen biotransformation and clearance. Given that the regulation of reproductive hormones and the BPG-liver axis are highly conserved, this study provides new insights into the hypoxia-induced endocrine disrupting mechanisms and reproductive impairment in other vertebrates.