{"id":974,"date":"2020-04-13T17:19:27","date_gmt":"2020-04-13T21:19:27","guid":{"rendered":"http:\/\/haidut.me\/?p=974"},"modified":"2020-04-13T17:19:27","modified_gmt":"2020-04-13T21:19:27","slug":"dht-may-be-vital-for-the-morphogenesis-of-organisms","status":"publish","type":"post","link":"https:\/\/haidut.me\/?p=974","title":{"rendered":"DHT may be vital for the morphogenesis of organism(s)"},"content":{"rendered":"

As many of my readers know, the potent androgen DHT is one of the most vilified endogenous substances produced by the human body, second only to cholesterol. Aside from verbal vitriol published in mainstream scientific journals, this attitude of medicine towards DHT can also be estimated from the number of prescriptions for 5-alpha-reductase (5-AR) inhibitors such as the (in)famous finasteride\/dutasteride (and less so androgen receptor antagonists such flutamine\/bicalutamide) as those are the main pharmaceutical tools in the “war” against DHT. Those drugs are mostly prescribed to males and the number of prescriptions is in the top five prescribed drugs, behind only statins, PPI (anti-acid drigs), and blood pressure drugs. As a result of those prescriptions, there is a large and ever-growing number of males who experience long-term psychological and physiological decline despite the vehement denials by mainstream medicine and Big Pharma that those drugs are risky or cause any long-term issues. These long-term issues from using 5-AR inhibitors are collective known as post-finasteride syndrome (PFS)<\/a>, and class-action lawsuits have already been launched against pharma companies for deliberately concealing the side effects of such drugs, which were apparently known even during their development.<\/p>\n

Now, another study demonstrates the crucial role of DHT not only in psychological and sexual health but also the very developmental fields that maintain the structure of the organism and give a living being its unique shape and behavior (phenotype). The study below demonstrates that exposure of snails to the 5-AR inhibitors finasteride and dutasteride dramatically disrupted the development of the snail’s shape as well as the viability of its embryos. Exposure to either drug resulted in uncoiled (banana-shape) instead of spiral (ram horns) shell shapes. The concentrations of the two drugs used was rather low and easily achievable by commonly prescribed doses of those drugs. Exposure to a slew of other steroidogenic inhibitors, statins, mutagens, or anti-flammatory chemicals did NOT result in shell disruption. This suggests that the morphogenesis function is unique to DHT and other known beneficial steroids such as progesterone, DHEA, testosterone, etc are not involved (much) in maintaining the shape of an organism. This morphogenesis function of DHT is unrelated to sexual effects as the snails do not use DHT for sexual development\/reproduction and do not express the androgen receptor (AR) (or any of the other steroid receptors for that matter). That means DHT has potent non-genomic (metabolic?) beneficial effects, through mechanisms which are just starting to be elucidated. What could those mechanisms be? Well, the study suggests that in other, similar types of snails, such disruption of shell shape is often caused by environmental stressors. In other words, DHT may be acting as a cardinal protector from such stressors or the 5-AR inhibitors are a potent type of such stressors. I think it is reasonable to suspect both are true until more is known.<\/p>\n

https:\/\/phys.org\/news\/2019-11-hormone-clue-snail-shells-spiral.html<\/a><\/p>\n

“…5-alpha-reductase (5\u03b1R) is the enzyme humans use to convert hormones needed to reproduce. Researchers turned off that same enzyme in developing snails and found their snails grew banana-shaped shells instead of spirals<\/strong>. “Normally they look like ramshorn shapes, very tightly curled,” said Dr Alice Baynes at Brunel University London. “But here they get very elongated, so something’s happening when we disrupt their 5\u03b1R”.\u00a0 “We’re not sure if not having the enzyme stops the shells from curling, or if the curl isn’t starting at the right angle. The enzyme is probably converting something into a\u00a0hormone<\/a> that helps shell patterning. They just get this really wide-open curl and when they keep growing for longer, their shells actually look like ring donuts.” In mammals, 5\u03b1R converts the male sex hormone testosterone into the stronger male sex hormone dihydrotestosterone (DHT)<\/span><\/strong>, an androgen which helps male development and reproduction. Snails and molluscs, like mussels and squid, also have the 5\u03b1R\u00a0enzyme<\/a>. But research shows that snails do not use either testosterone or DHT for reproductive development<\/span><\/strong>. So scientists wanted to discover what snails do use these hormones for.”<\/p>\n

“…In a study in Nature’s latest\u00a0Scientific Reports<\/i>, the team used the drug dutasteride<\/span> \u2013 which treats enlarged prostates \u2013 to block 5\u03b1R enzymes in growing snail embryos<\/strong>.\u00a0 “We found a surprising effect on snail shell development<\/strong>,” said Dr Baynes. “The snail embryos grow elongated ‘banana-shaped’ shells instead of tightly curled shells<\/strong>“.\u00a0 “This disruption to shell shape is not what we might expect in a mammal or a fish, which would be reduced male characteristics or sperm production. Our findings indicate 5\u03b1R has an essential role in\u00a0snails<\/a><\/strong>\u00a0and could lead to a better understanding of hormones and\u00a0shell<\/a>\u00a0development in molluscs.\u00a0\u00a0It’s an interesting first step.”<\/p>\n

https:\/\/www.nature.com\/articles\/s41598-019-52850-x<\/a><\/p>\n

“…In four independent experiments, dutasteride<\/span> (DUT) induced an elongated banana-shaped shell phenotype in a dose-dependent manner<\/strong>. The average minimum banana-shaped phenotype response (1% of embryos had banana-shaped shell phenotype) was observed at a dose of 10\u2009\u00b5g\/L, and the average maximum response (89% of embryos had banana-shaped shell phenotype) at the highest tested dose of 160\u2009\u00b5g\/L DUT. The banana-shaped shell phenotype became significantly elevated compared to the solvent control at 40\u2009\u00b5g\/L DUT (P\u2009<\u20090.0001) and higher concentrations (Fig.\u00a04<\/a>). Finasteride<\/span> (FIN) also induced the banana-shaped phenotype and its effects were also dose-dependent, although it was less potent than DUT, with the average<\/strong> (based on four independent experiments) minimum response (3% banana-shaped) at 300\u2009\u00b5g\/L and the maximum (82% banana-shaped) at 1520\u2009\u00b5g\/L (Fig.\u00a04<\/a>). FIN significantly induced the banana-shaped phenotype at 450\u2009\u00b5g\/L FIN (P\u2009<\u20090.0001) and above. In both the DUT and FIN experiments, the number of embryos classed as \u2018normal\u2019 was inverse to the banana-shaped phenotype and was significantly reduced in a dose-dependent manner<\/strong><\/span>. The percentage of other malformations or embryos that died\/did not develop remained stable across the experiments and there was no significant effect (P\u2009>\u20090.05) of DUT or FIN concentration for these endpoints.”<\/p>\n

“…Eight other compounds, including three other pharmaceutical steroidogenic enzyme inhibitors<\/strong> (Galeterone (GAL); CYP17A1 inhibitor, Trilostane (TRI); 3\u03b2-HSD inhibitor, Atorvastatin (ATO); HMG-CoA reductase inhibitor), one 5\u03b2-reductase inhibitor<\/strong> (Chenodeoxycholic acid (ChenA)), a mutagen<\/strong> (Benzoquinoline (BENZO)), and an anti-inflammatory chemical<\/strong> (\u03b3-linolenic acid (y-LIN) were tested in the embryonic\u00a0B. glabrata<\/i>\u00a0assay to assess whether the banana-shaped phenotype was specific to 5\u03b1R inhibitors, or if it was a general enzyme-inhibition or toxicity effect<\/strong>. None of the other compounds tested elicited the banana-shaped phenotype<\/strong> (Supporting Information Table\u00a0S4<\/a>)…Dorsomorphin<\/strong> (DORS) was included as it had previously been reported to induce \u2018immature shell-shape\u2019 or cone-shaped<\/strong> (non-coiling) phenotypes<\/strong> in the gastropod\u00a0Lymnaea stagnalis<\/i>\u00a0(at 0.5 and 1\u2009\u00b5M, depending on exposure window)47<\/a><\/sup>. However, no banana-shaped phenotype or non-coiling embryos were observed in any of the DORSO concentrations we tested<\/strong> (Supporting information Table\u00a0S3<\/a>)…In summary, none of the other compounds tested<\/strong> (pharmaceutical enzyme inhibitors or experimental chemicals) induced the banana-shaped phenotype in developing\u00a0B. glabrata<\/i>\u00a0embryos<\/strong> (Supporting information Tables\u00a03<\/a>). Only the potent pharmaceutical 5\u03b1R inhibitors elicited the developmental effect of shell malformation<\/strong><\/span>. Which suggests that the 5\u03b1R inhibitors were specifically impacting a particular enzyme vital to\u00a0B. glabrata<\/i> morphological development.”<\/p>\n

“…To test whether the pharmaceutical 5\u03b1R inhibited phenotype was species-specific, a small experiment was conducted with a second freshwater gastropod species,\u00a0Physella acuta<\/i>.\u00a0P. acuta<\/i>\u00a0embryos were developmentally exposed to solvent control, 100 and 200\u2009\u00b5g\/L DUT. This experiment induced strikingly similar results to\u00a0B. glabrata<\/i>, <\/strong>with 71.2 and 82.6% of the embryos developing the elongated banana-shaped phenotype in the 100 and 200\u2009\u00b5g\/L DUT respectively (Fig.\u00a05<\/a>, Supporting information Table\u00a0S5<\/a>). Both DUT doses tested produced significant induction (P\u2009<\u20090.0001) of banana-shaped snails compared to the solvent control, with the reciprocal reduction in normal shaped embryos. As seen with\u00a0B. glabrata<\/i> no significant effects of DUT dose were found for the number of non-specific malformations (P\u2009>\u20090.9999, P\u2009=\u20090.8770, respectively) or deaths (P\u2009=\u20090.9282, P\u2009>\u20090.9999, respectively).”<\/p>\n

“…A number of gastropods, such as those within the Vermetidae50<\/a><\/sup>\u00a0and the Caecidae families51<\/a><\/sup>\u00a0produce shells that are elongated in shape compared to typical coiled gastropod shells<\/strong>. Variation in coiling can also be seen within freshwater gastropods, and there is some debate about whether these curious findings are distinct species or if the unusual shell growth is a sporadic aberrant phenotype52<\/a><\/sup>. Recent investigations into a corkscrew-like shell of the typically planispiral-shaped\u00a0Gyraulus<\/i>\u00a0sp., discovered in a remote Tibetan lake, suggest these phenotypes are the result of as-yet-unknown ecological stressor<\/span> rather than speciation<\/strong>52<\/a><\/sup>. ”<\/p>\n

“…Here we demonstrate that pharmaceutical 5\u03b1R inhibitors induced a strong and highly reproducible phenotypic response<\/span> <\/strong>in developing\u00a0B. glabrata<\/i>\u00a0and\u00a0P. acuta<\/i>\u00a0embryos that is not associated with toxicity<\/span><\/strong>. We have also confirmed that both 5\u03b1R homologues identified in\u00a0B. glabrata<\/i>\u00a0are expressed during embryonic development and that antibodies raised against human 5\u03b1Rs proteins are reactive in\u00a0B. glabrata<\/i>\u00a0embryo extracts; this strongly suggests that pharmaceutical 5\u03b1R inhibitors could be acting on\u00a0B. glabrata<\/i>\u00a05\u03b1R enzymes to cause this phenotypic disruption. In adult\u00a0B. glabrata<\/i>, 5\u03b1Rs transcripts have been detected in mantle tissue32<\/a><\/sup>. This is of note as molluscan shells are formed from secretory cells in the mantle21<\/a><\/sup>, providing a possible link between 5\u03b1R and shell formation.”<\/p>\n","protected":false},"excerpt":{"rendered":"

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