Sex Hormone-Binding Globulin in Fish Gills Is a Portal for Sex Steroids Breached by Xenobiotics

As in most vertebrates, plasma sex hormone-binding globulin (SHBG) is produced in fish liver and regulates sex steroid access to target tissues. Low levels of SHBG mRNA are present in zebra fish gills but are unlikely to account for the high amounts of immunoreactive SHBG in filaments and lamellae. Although the uptake of steroids by fish from water has been reported to correlate with their affinity for SHBG, it is not known how this occurs. Our studies of zebra fish SHBG have revealed its preference for biological active androgen (testosterone), as well as for androstenedione, a sex steroid precursor that also acts as a pheromone in some fish. In addition to natural steroids, zebra fish SHBG has a high affinity for synthetic steroids, such as ethinylestradiol and progestins (levonorgestrel and norethindrone), that are present in waste water systems. Because steroids can pass across fish gills, we examined whether SHBG serves as a portal for natural and synthetic steroids controlling their flux between the blood and aquatic environment. The results indicate that SHBG ligands are rapidly and specifically removed from water by the fish through their gills, whereas the accumulated steroids are released slowly. The capacity of fish to sequester SHBG ligands from water is similar between sexes, independent of size, and characterized by a wide dynamic range. We conclude that SHBG controls the flux of sex steroids across fish gills and that this highly specialized function can be hijacked by xenobiotic ligands of fish SHBGs.