The arachidonic acid cascade is involved in the masculinizing action of testosterone on embryonic external genitalia in mice.

Abstract

We have evaluated whether the arachidonic acid cascade may be involved in the folding and fusion of the penis and scrotum in masculine differentiation, a possibility raised by recent observations of the involvement of the arachidonic acid cascade in the analogous embryonic processes of elevation and fusion of the palatal shelves and of folding and fusion of the neural tube. To test this hypothesis, during embryonic masculine differentiation in mice of the B1O.A strain, we administered certain agents that produce blockade of masculinization. We report that arachidonic acid can reverse the inhibition of masculine development in male embryos produced by estradiol-17/8 or by cyproterone acetate, an androgen receptor-site blocker, and that such reversal can be prevented by an inhibitor of cyclooxygenase, such as indomethacin. We have also found that agents that block the arachidonic acid cascade at the level of phospholipase A2 (cortisone, phenytoin) or at the level of cyclooxygenase (indomethacin, aspirin) also block masculine differentiation and that such antimasculinization is reversed by arachidonic acid. The masculinization of male embryos is inhibited by indomethacin and aspirin, and the masculinization of female embryos produced by exogenous testosterone is prevented by indomethacin. These findings provide evidence that the mechanism by which testosterone organizes the genitalia involves a role of the arachidonic acid cascade leading to prostaglandins at a critical period of development and that interference with testosterone synthesis or action leads to a teratogenic deficiency of arachidonic acid during this time in the genital anlagen.Mammalian embryos of either genetic sex have initially an indifferent genital tubercle, which develops into a penis and scrotum, if there is a functioning embryonic testis or if there is not, by administration of testosterone to the mother; otherwise, the inborn female program is expressed (1). Agents that interfere with the synthesis (e.g., estradiol-17/3), circulation, or action of testosterone (e.g., cyproterone acetate) block masculine differentiation of the genitalia of genetically male embryos, as manifested by the production of hypospadias-i.e., a displacement of the urethral orifice down the shaft of the penis from the tip with a shortening of the anogenital distance (2-10). The means by which testosterone organizes masculine differentiation of the genitalia in the embryo depends on classical androgen hormonal receptor mechanisms (5, 9, 11). However, the precise steps involved in this organizing action of testosterone in the embryo are not known.A clue to the possible nature of these steps has been given by evidence (12,13) suggesting that the arachidonic acid cascade leading to prostaglandins may be involved in the elevation and fusion of the embryonic shelves in differentiation of the palate. This suggestion is based on the findings that (i) arachidonic acid reverses both the incidence of cleft palate induced in mice and rats by glucocorticoids in vivo and th...

Intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders in human and rat

“…Since this is only three times the dose recommended for humans of 50 mg/kg/day, further work is needed to determined the no adverse effect level. Effects after exposure to acetylsalicylic acid in the rats were more severe than after paracetamol and resulted in fetal growth retardation, which is in line with previous reports (Gupta et al, 2003), and reduction in testosterone production as also described in mouse studies (Gupta and Goldman, 1986). Examination of mild analgesics' effects directly on the initiation of fetal testosterone production in GD14.5 rat testes further supported the notion of a direct anti-androgenic effect.…”

“…This could suggest that these endocrine disrupting compounds damage male reproductive function by inhibiting PG synthesis. This hypothesis is supported by the previous indications that mild analgesics, which relieve pain and reduce inflammation by reducing PG synthesis, may reduce testosterone production (Gupta and Goldman, 1986;Gupta, 1989). If so, pharmaceutical PG inhibitors, at the doses used by humans, could act as endocrine disruptors.…”

“…In both Europe and the USA, more than 50% of pregnant women report intake of mild analgesics with the majority using paracetamol (Werler et al, 2005;Rebordosa et al, 2008b). Studies from the 1980s have suggested a link between prenatal exposure to mild analgesics and reduced masculinization in animals (Gupta and Goldman, 1986;Gupta, 1989). This is of concern, since several reports have indicated an increase in the incidence of male reproductive disorders over the recent decades (Swan et al, 1997;Boisen et al, 2004Boisen et al, , 2005Richiardi et al, 2004) and the geographical distribution together with migration studies (Hemminki and Li, 2002) have suggested that lifestyle and environmental factors play key roles in the pathogenesis.…”

Monster Phase of Acetaminophen Use in Pregnancy: Current Vision of an Old Drug

“…Undescended testes may be linked with alarming risk of testicular germ cell tumors, reduced fertility and psychological adverse events when the baby is grown [17]. Prostaglandins are assumed to be implicated in the differentiation of the testis and the male genital tract [18,19]. Different hormones interplay in the development of the male reproductive system and thus extremely predisposed to endocrine disruption [20].…”

Molecular Genetic and Endocrine Mechanisms of Hair Growth

“…The transcriptional regulatory activity of liganded AR requires association with a variety of tissue-specific co-regulatory proteins and other transcription factors whose identities and functions are beginning to be understood [33]. In the end, the effects mediated by androgen are highly variable; in genitalia the arachidonic acid cascade is activated [39], while in epiphyseal cartilage the IGF-1 system is stimulated [40]. …”