Effects of caffeine and its reactive metabolites theophylline and theobromine on the differentiating testis

Abstract

A previous study in the rat (Pollard et al. 1990) established that caffeine, when administered during pregnancy, significantly inhibited the differentiation of the seminiferous cords and subsequent Leydig cell development in the interstitium. However, that study could not distinguish between the direct effects of caffeine and/or the intermediary secondary toxic effects of metabolites such as theophylline and theobromine. Because the fetus lacks the appropriate enzyme systems, clearance of toxic substances takes place via the placenta and maternal liver. Thus, a suitable in vitro system can effectively differentiate between primary and secondary drug effects. In the present study, 13-day-old fetal testis, at the stage of incipient differentiation, were cultured for 4 days in vitro in the presence of graded doses of caffeine, theophylline or theobromine. It was found that explants exposed to caffeine or theobromine differentiated normally, developing seminiferous cords made up of Sertoli and germ cells, soon followed by the differentiation of functionally active Leydig cells appearing in the newly formed interstitium. However, explants exposed to theophylline failed to develop seminiferous cords and, as a consequence, Leydig cells. In conclusion, insights obtained from different experimental methods, such as organ culture or whole organism studies, are not always identical. It may be prudent, therefore, to take into account that certain experimental techniques, despite providing valuable information, may require confirmation by other test methods in order to obtain an in-depth understanding of mechanisms of action involved.

Endocrine Disruption in Human Fetal Testis Explants by Individual and Combined Exposures to Selected Pharmaceuticals, Pesticides, and Environmental Pollutants

“…Not only did this effort provide detailed dose–response data about many chemicals already known to be active in the FEGA ( Ben Maamar et al 2015 ; Eladak et al 2015 ; Mazaud-Guittot et al 2013 ; Pont et al 1982 ), it also uncovered several new chemicals whose capability of suppressing testosterone synthesis in humans was not previously recognized: the pesticide imazalil, which had been described before as an androgen receptor antagonist in the MDA-kb2 cell line ( Orton et al 2011 ); the pesticides propiconazole and bitertanol, which had been previously shown to decrease the testosterone production in the NCI-H295R cell line ( Taxvig et al 2013 ), and the fungicide prochloraz and the selective estrogen receptor modulator clomifen, both known to be anti-androgenic in the rat ( Laier et al 2006 ; Fontenot et al 2015 ). Theophylline, a caffeine metabolite and pharmaceutical used in the treatment of asthma had previously been shown to impair Leydig cell development in the rat ( Pollard et al 2001 ). Our data also revealed anti-androgenic properties of the teratogenic drug valproic acid and the pesticide chlordecone ( Figure 1A,B , Table 1 ).…”

Maternal caffeine consumption has irreversible effects on reproductive parameters and fertility in male offspring rats

“…However, it was found that 13-day-old fetal testis explants exposed to graded doses of caffeine or theobromine for 4 days in vitro differentiated normally, developing seminiferous cords made up of Sertoli and germ cells. In contrast, explants exposed to theophylline, another metabolite of caffeine, failed to develop seminiferous cords [42]. Moreover, atrophy of the seminiferous tubules with small patchy areas was reported in adult Albino rats that had been given 40 to 50 mg/kg/day caffeine [43].…”

“…However, it was found that 13-day-old fetal testis explants exposed to graded doses of caffeine or theobromine for 4 days in vitro differentiated functionally active Leydig cells appearing in the newly formed interstitium. In contrast, explants exposed to theophylline, another metabolite of caffeine, failed to develop normal Leydig cells [42]. Furthermore, it has been shown that the sons of mothers drinking 4-7 cups of coffee per day had lower testosterone levels than the sons of mothers drinking 0-3 cups per day ( p <0.04) [19].…”

Effect of maternal coffee, smoking and drinking behavior on adult son's semen quality: prospective evidence from the Child Health and Development Studies

“…These studies have demonstrated a direct impact of the caffeine metabolite, theophylline, on the development of the seminiferous cords, embryonic precursors to the Sertoli cells. 29 Studies have also shown that coffee alters hormone levels in humans, lowering estrogen 30 and increasing testosterone and sex hormone-binding globulin, 31 laying a foundation for another mechanism by which developing gonadal cells might be affected by prenatal coffee exposure.…”