PRINCIPLES OF TOXICOLOGY - Biology East Borneo

11.1 MALE REPRODUCTIVE TOXICOLOGY 213elements called protamines during later stages of spermatogenesis and protamines are particularlyvulnerable to reactions with ethylene oxide.These medically related examples indicate the delicate balance between therapeutic or beneficialuses and potential reproductive toxicity. The powerful alkylating properties of chemotherapy drugsallow them to work against rapidly dividing cancer cells and the risk of ancillary effects on other cells,even frank reproductive toxicity, may represent an acceptable tradeoff for the cancer patient. Also, thesafety and benefits of dry, gas sterilization with ethylene oxide are clearly significant. While we candocument the mechanisms of action producing male reproductive toxicity experimentally, there is noevidence that the ethylene oxide exposures associated with sterilization has produced reproductivetoxicity in men. Again, the toxicology indicates what could happen if the right conditions existed, notwhat happens under the typical situations in which the chemicals are encountered.Many of the compounds of interest in occupational or environmental toxicology require metabolicactivation to produce reproductive effects. The testis has the enzymatic capabilities for oxidativemetabolism, a pathway that frequently produces reactive intermediates. While this activity is lowcompared to the liver, it is sufficiently high to produce toxic amounts of metabolites for somecompounds.Metabolism of common industrial chemicals including the solvents n-hexane and the glycol ethersappears to contribute to their reproductive toxicity. Some of the phthalates, a chemical class usedextensively as plasticizers and distributed widely in the environment, are also capable of affecting malereproductive tissues after metabolism. All of these examples are discussed further with regard to thespecific cells they affect and have at least purportedly affected humans. There are also many otherexamples of indirect acting male reproductive toxicants where there is at least experimental ormechanistic information on toxic potential including the intermediate acrylamide and vinyl chloride,another common industrial intermediate also found in the environment, often as a breakdown productof dry cleaning solvent.Cell-type Specific ToxicityAnother principle illustrated by examining male reproductive toxicology is the specificity of action oncertain cell types due to the characteristics of the cells or their metabolic potential. For somereproductive toxicants, there is varying sensitivity among the somatic and germ cell types. While thismay be explained in some cases by the high levels of cell division and activity among the germ cells,in some cases there appear to be more specific factors involved. Besides the germ cells, there are twomajor types of somatic cells in the testis required for spermatogenesis, Sertoli cells and Leydig cells.Both of these cell types may also be specific targets for some toxicants. In addition, the microvasculatureof the testis can be a specific target and the functional consequences of impaired circulation inthe testis have been described above.Developing Sperm Cells As germ cells proceed through spermatogenesis, several different terms areused to distinguish the varying degrees of maturity. At the earliest stages are the spermatogonia,followed by the spermatocytes, the spermatids, and finally spermatozoa (Figure 11.1). Besidesdescribing the developmental stage of the germ cells, these distinctions also correspond to some degreeof toxicological specificity as certain stages are targeted by certain compounds. This specificitygenerally relates to which stages are the most sensitive to a particular agent. In most cases, as the doseincreases or exposure conditions change, more than one stage can be affected.One of the occupational episodes that stirred interest in effects on male reproductive function wasreported sterility among workers handling the pesticide dibromochloropropane (DBCP). Subsequentinvestigations suggested a toxic effect that would certainly explain sterility. The most significant celltype damaged by DBCP is probably the spermatogonia. Since these progenitor germ cells are at thebase of spermatogenic cellular expansion, their destruction precludes future cycles of spermatogenesis.Thus, the expected observation would be a depletion of all the later stages and an inability to recover