Adaptive Biochemical Repair Response Toward Germ Cell DNA Damage

Abstract

The Final expression of chemical toxicity is determined by pharmacokinetic, pharmacodynamic, homeostatic, and adaptive favors. In order to understand differential toxicity at the cellular and organ levels, one must outsider Ow main factors which may modulate the toxic effects of chemicals. In the male gonads, such modifying factors are the bloodtestis barrier which restricts the testicular penetration of many foreign chemicals, differentially distributed mixed‐function oxidase(s) between the germ cell and interstitial cell compartments, and the presence of differing DNA repair capacities in the various stages of spermatogenic cells. DNA repair systems are present in spermatogonia and spermatocytes, while more mature spermiogenic cells (spermatids and testicular sperms) appear deficient in DNA repair capabilities. Furthermore, strain and species differences in the germ cell's ability to repair DNA suggest a diverse response of germ cells to DNA‐damaging agents. The capacity of prespermiogenic cells to respond to damage induced by certain chemical mutagens accounts for stage‐specific spermatogenic cell toxicity. Mono‐functional alkylating agents such as methylmethane sulfonate (MMS) cause single strand DNA breaks in prespermiogenic cells which are repaired expeditiously, while the same germ cell types are unable to repair DNA damage induced by bifunctional or polyfunctional alkylating agents. DNA damage induced by polyfunctional alkylating agents involves inactivation or DNA template as a result of inter‐ and/or intrastrand DNA, which is more slowly repaired with greater error frequency in the newly‐synthesized DNA. Thus, both bifunctional and polyfunctional alkylating agents are more toxic to male germ cells than are the monofunctional atkylating agents. DNA damage measured by the alkaline elution analysis appears to be a relatively simple, sensitive indicator of germ cell DNA damage. The DNA repair system appears to be another protective mechanism against monofunctional alkylating agents such as MMS, while the same adaptive system is ineffective in overcoming the effects of bifunctional or polyfunctional alkylating agents. DNA repair rates need to be quantified and factored into the phamacokinetic model being developed for extrapolation from laboratory animals to man.

Evidence suggesting that germ cells influence the bidirectional secretion of androgen binding protein by the seminiferous epithelium demonstrated by selective impairment of spermatogenesis with busulphan

“…Another alkane sulphonate, butylene dimethanesulphonate (busulphan), alkylates DNA and selectively destroys spermatogonia in vivo without affecting testosterone production. As the remaining germ cells mature, maturation depletion results in a selective and progressive absence of germ cell types, following which there is repopulation of the seminiferous epithelium (Jackson, Partington & Fox, 1962;Lee, 1983). The present study, using busulphan-treated rats, suggests that specific germ cells differentially regulate the bidirectional secretion of ABP.…”

Flow cytometric analysis of mouse spermatogenic function following exposure to ethylnitrosourea

“…A 0 interaction with depurinated DNA. Alkylated regions of DNA are recognized by a complex enzyme system that excises the modified base from the DNA strand, degrades it, and resynthesizes the damaged section to reconstitute the complementary DNA strands 28 days prior to measurements, it seems likely that (30). One might speculate that if the repair process were not completed prior to nuclear condensation, depurinated regions might exist that could hypotheticaly interact with A 0 to produce red fluorescence.…”

“…ENU is a potent alkylating chemical that results in germ cell DNA strand breaks (37). However, since exposure to ENU was repair would have been completed by this time; for example, most MMS-induced DNA strand breaks in mouse testicular cells are apparently repaired by 72 h (30). Conversely, repair of DNA strand breaks has in some cases been shown to take weeks (15).…”