PRINCIPLES OF TOXICOLOGY - Biology East Borneo

210 REPRODUCTIVE TOXICOLOGYcontinues to shift toward non-industrial occupational exposures and general environmental exposures,many new discoveries about the mechanisms of toxic injury to the female reproductive system anddeveloping offspring can be expected.Most of the best described examples of reproductive toxicity rely on experimental results obtainedwith laboratory animals for their explanations. While inferring the actual human potential for anadverse occurrence from animal testing results must always be done critically and cautiously, there arecertain factors relating to reproductive endpoints that add unique uncertainties. The relevance of theexperimental dose level to potential human exposures is always an important factor for interpretinganimal studies. For reproductive endpoints, not only is the dose level an issue, the duration and intervalused for dosing is also critical since sequential, delicately timed progressions of physiological eventsare a hallmark of reproductive processes. Experimental testing for any given chemical must encompassthe timeframe likely to be relevant for the mechanisms of toxicity involved. In evaluating developmentaltoxicity, concomitant maternal toxicity can be a problematic complication. In trying to demonstrateeffects, dose levels are often pushed high enough to result in general wasting, nutritional problems, orother stresses on the animal. Thus, it can be difficult to distinguish between direct toxicity to thedeveloping offspring and females that are simply too compromised to maintain a normal pregnancy.With such complications firmly in mind, animal testing remains a critical and valuable tool forcharacterizing reproductive toxicity. There is no way around the need for test systems that can bereadily manipulated to tease out potential mechanisms of toxicity. The challenge is interpreting theimplications of particular animal testing results and determining how they relate to potential concernsfor humans.11.1 MALE REPRODUCTIVE TOXICOLOGYIn the most basic sense, the functions of the male reproductive system are to produce and deliver themale germ cells, spermatozoa, in such condition that union with a female germ cell and subsequentdevelopment can occur. Toxic responses must interfere with either germ cell production or delivery.The reproductive organs are obvious targets for such responses, but damage in the nervous andendocrine systems can also be important due to their role in controlling reproductive function. Thissection will describe some of the toxic chemicals that affect germ cell production and their mechanismsof action. Additionally, information about some of the toxic responses that can cause problems withsperm delivery will be presented.Susceptibility of SpermatogenesisThe process of germ cell production in the male, spermatogenesis, provides clear examples ofhow cells may have enhanced susceptibility to certain classes of chemicals at particular times. Inspermatogenesis, germ cells are produced from a pool of progenitor cells, stem cells, through aseries of mitotic and meiotic divisions that eventually produce a large number of spermatozoafrom each original stem cell and provide replacement stem cells. Spermatogenesis occurs inspecialized, thick walled tubules within the testis called seminiferous tubules. The germ cells areinitially located at the outer edge of the tubule (Figure 11.1) and move progressively toward thecenter of the tubule. From here the spermatozoa move along the tubules and into the duct systemthat will carry them out of the body.In a human, it takes about 64 days to produce a mature spermatozoon through this process, whichcontinues throughout adult life. The rate of spermatogenesis increases dramatically following pubertyuntil a hundred million or more sperm are produced each day. Spermatogenesis can be equated to amass production process where constant high rates of production and high quantity of output are thefocus. In a biological system, this requires an extremely active, rapidly dividing cellular environmentwithin the testis.