Factors influencing reproduction and genetic toxic effects on male gonads.

The objective of toxicological study of a target organ, such as the testis, is to elucidate the qualitative and quantitative toxic effects of a chemical on that organ. The ultimate objective is to assess the toxic effects of a chemical in laboratory animals and extrapolate the pertinent experimental data to man. To accomplish these objectives, one must consider the main factors which may influence and modulate the toxic effects of chemicals in the organ. In the male gonads, such modifying factors are the pharmacokinetic parameters governing the absorption, distribution, activation and detoxification of indirect carcinogens, covalent bindings to macromolecules, and DNA damage as well as DNA repair of damaged germ cells. All of these factors have been presently studied in our laboratory and are discussed in this paper with the exception of covalent bindings to macromolecules.The pharmacokinetic studies demonstrated that the functional blood-testis barrier (BTB) closely resembles the blood-brain barrier in transport characteristics: the permeability of nonelectrolytes and the acidic drugs with pK(a) values depend upon their molecular size and their partition coefficients, respectively. Thus, the functional BTB, restricts the permeability of many foreign compounds to male germ cells. Studies of mixed function oxidases and cytochrome P-450 system in male gonads demonstrated that the presence of AHH, EH, and GSH-ST implicate activation and detoxification of polycyclic hydrocarbons. Thus, active electrophiles may exert significant toxic effects locally within both interstitial and germ cell compartments. The presence of an efficient DNA repair system in premeiotic spermatogenic cells (and not in spermiogenic cells) can further modify both toxic and mutagenic events in the subsequent differentiation of germ cells to mature spermatozoa.