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  • The role of DHT in early teleost embryogenesis

    2022-11-18

    The role of DHT in early teleost embryogenesis is not entirely clear or established, however additional studies that treat fish embryos to DHT or to specific srd5a inhibitors at critical stages of development (i.e. prior to RQ-00203078 sex differentiation) will shed light on the early functions of this androgenic steroid (Table 1). Langlois et al. (2010b) are one of the few groups to investigate the effects of 5 alpha-reductase inhibition during the initial days of development in non-mammalian species. Using Western clawed frog embryos, the researchers demonstrated that inhibiting enzyme activity using finasteride (specific Srd5a2 human inhibitor) led to significant decreases of srd5a2 mRNA levels in frog larvae (Nieuwkoop-Faber stage 46), and the authors proposed that DHT regulates srd5a2 transcription during embryogenesis. No changes were observed for both srd5a1 and srd5a3, indicating differential regulation of mRNA levels for the three srd5a isoforms. Few studies have investigated the effects of androgens or anti-androgens during critical windows in early fish and frog development as most studies sub-chronically expose the animals in order to observe changes in sex ratios. There are some studies showing that fish exposed to DHT or DHT-like compounds at the RQ-00203078 of embryogenesis exhibit masculinization (Bogers et al., 2006, Iwamatsu et al., 2006a, Iwamatsu et al., 2006b). However, sensitive periods to DHT vary among species as their life cycles are different. In FHMs, a minimum of 63d of exposure to 17α-methyl-DHT (MDHT) was needed to observe signs of masculinization; whereas after 114d exposure, there was a significant increase in detectable biological effects with the most effective concentrations being 0.1 and 0.2μg/L MDHT (Bogers et al., 2006). In another fish species (O. latipes), MDHT led to sex reversed female phenotype following 10d exposure; while higher concentrations increased the incidence of sex-reversed males (Iwamatsu et al., 2006a, Iwamatsu et al., 2006b). In general, adult fish that were chronically exposed to either MDHT or DHT exhibit male secondary sex characteristics (SSCs), including increase incidence and prominence of nuptial tubercles, biased male sex ratio, and decreases of plasma vitellogenin (Vtg) levels, a protein normally synthesized in the liver in response to circulating estrogens (Table 1; Bogers et al., 2006, Iwamatsu et al., 2006a, Iwamatsu et al., 2006b). Few studies have investigated the effects of sub-chronic DHT treatments during frog development. Exposure to DHT resulted in effects to larynx development in African clawed frog froglets (Carr et al., 2003, Coady et al., 2005, Robertson et al., 1994) and no biased sex ratios were observed (Carr et al., 2003, Coady et al., 2005). However, 1mg/L DHT reduced ovarian differentiation, while increasing the incidence of undifferentiated individuals in the common toad (Bufo bufo; Petrini and Zaccanti 1998). In contrast, finasteride treatment induced a biased sex ratio in Western clawed frog chronically exposed to the pharmaceutical, decreasing the proportion of animals that displays male phenotype (Duarte-Guterman et al., 2009). Taken together, these studies demonstrate that waterborne exposure to DHT results in the induction of male SCCs in both fish and frogs. A final point to make is that in early staged teleost fishes and amphibians, it is still not entirely clear what the roles of androgens are during development. For example, the presence of testosterone in oocytes may be due to active uptake of vitellogenin and other lipids during oogenesis. Steroids such as testosterone are able to physically interact with lipoproteins (Gershfeld and Muramatsu, 1971), and the presence of testosterone in oocytes may not reflect a regulated process. Thus, detectable levels of testosterone in embryos may be a consequence of high steroids in the maternal plasma. Conversely, to support the hypothesis that testosterone and DHT have a role in early development, studies have demonstrated that the machinery required for converting testosterone into the more potent androgen DHT (i.e., steroid 5-reductases) as well as binding androgens (i.e., the androgen receptor) is present in the frog egg (Langlois et al., 2010b; Langlois and Martyniuk, 2013), and these genes increase in expression over early development. The presence of all three steroid 5-reductase enzymes and protein during early development suggests that testosterone may be converted into DHT in order to regulate embryonic cellular processes unrelated to sexual development. The presence of testosterone during early development may also be necessary as a precursor for the synthesis of estrogens which are well documented to be involved in early sex development in fish (Tong et al., 2010) and are biologically active at 5–10dph in FHMs based upon vitellogenin induction (Van Aerle et al., 2002). Despite evidence that enzymes in steroidogenic pathways are expressed early in development, there is much to research in terms of functional significance within the embryo.