A Practical Approach, Second Edition=Ronald D. Ho.pdf

ROLE OF XENOBIOTIC METABOLISM IN DEVELOPMENTAL AND REPRODUCTIVE TOXICITY 557reversal of DBCP toxicity was noted in oligospermic but not in azoospermic men. In rats, GSHconjugates are formed from DBCP in liver, kidney, and testis cytosol. 254 The identification of theultimate toxicant has been illusive, 257 but an Ames assay suggested that oxidative metabolism isneeded to generate genotoxic metabolite(s) from DBCP. 257Chlordecone (kepone) causes reversible testicular toxicity and low sperm count, decreasedsperm motility, abnormal morphology, and arrest in sperm maturation in exposed men. 258 In humans,as in animals, a small portion of kepone in the body is reduced to its alcohol or converted toglucuronides and/or GSH conjugates before fecal excretion. Whether kepone itself or one of itsmetabolites is the reproductive toxicant is not yet established. Among pesticides, linking exposuresto Agent Orange (a 1:1 mixture of 2,4-D and 2,4,5-T herbicides) sprayed in Vietnam to systemicillnesses in soldiers and increased incidences of miscarriages, stillbirths, and birth defects has beenfrustrating, illusive, and hotly debated for the past 30 years. Many conflicting reports have appearedin the literature. It has been suspected that TCDD contamination, which occurred during themanufacture of 2,4,5-T, may be a culprit.Testicular cancer due to exposure to soot in chimney sweeps was documented long ago. Sincethen, several polycyclic aromatic hydrocarbons (PAHs) are suspected to cause testicular toxicity.Many studies have documented that smoking adversely affects testicular function in men. Asignificant decrease in sperm count and motility and an increase in abnormal sperm morphologyhave been documented. Although over 3000 different chemicals occur in the cigarette smoke, PAHsand a few other compounds are the suspected toxicants. The blood-testis barrier does not preventexposure of the testis to PAHs, such as BP. P450-catalyzes epoxidation of BP to the proximate BPdiol.Further oxidation forms the ultimate 7,8-diol-9,10-epoxide, which is believed to exert toxicity.Evidence gathered in rats by use of perfusion of the testis and testis homogenates indicates thattesticular enzymes can activate BP as well as detoxify toxic reactive intermediates. 252,253 Theplasticizer diethylhexyl phthalate and its metabolite monoethylhexyl phthalate, resulting fromdealkylation, are testicular toxicants in rodents. 259 They cause sloughing of spermatids and spermatocytesand vacuolization of Sertoli cell cytoplasm. 2,5-Hexanedione, a metabolite of n-hexane,is a testicular toxicant, 260 but it is not known whether testicular P450 mediates this reaction. Ethyleneglycol monoethyl ether and its metabolite, 2-methoxy ethanol (2-ME), are testicular toxicants. 2612-Methoxyacetic acid, the oxidation product of 2-ME generated by sequential oxidation by alcoholdehydrogenase and acetaldehyde dehydrogenase, is believed to be the ultimate testicular toxicant.Among drugs, several agonists or antagonists of natural hormones, antineoplastic agents, anesthetics,and antibiotics are known to produce adverse effects on the male reproductive system.Cyclophosphamide is a therapeutic agent commonly used for the treatment of boys with nephroticsyndrome and Hodgkin’s disease. The results of a few studies have suggested that high drugexposure, especially later in the puberty, is associated with elevated risks of decreased spermatogenesis.Although the enzymes responsible for cyclophosphamide bioactivation in testis are notknown, published data suggest that P450, PGS, and LO are capable of its conversion to acroleinand phosphoramide mustard. 72,73 Among antipsychotic agents, chlorpromazine has been shown toincreases the rate of prolactin secretion that may be associated with breast engorgement in men.Chlorpromazine is metabolized by several heme containing proteins and LO. Therapeutic use ofimipramine and amitriptyline causes delayed orgasm in some men, while other antidepressantshave been shown to suppress spermatogenesis. Imipramine and related tricyclic compounds areknown to be metabolized by P450 and flavin-containing monooxygenase, as well as by LO. 219C. Female Reproductive System1. Ovarian Enzymes of Xenobiotic MetabolismThe evidence suggests that the ovary has the full complement of enzymes necessary for metabolismof xenobiotics. Thus, the demonstration of AHH activity and BP metabolism indirectly suggest the© 2006 by Taylor & Francis Group, LLC