The Effect of Alkylating Agents on Male Rat Fertility

Abstract

The effects of tumour inhibitory doses of tretamine (triethylenemelamine), busulphan, and melphalan on the fertility of male rats have been examined. The aromatic nitrogen mustard, melphalan, was inactive, but busulphan has a highly selective action on spermatogenesis which contrasts strikingly with that of tretamine. The main action of tretamine was exerted upon spermatocytes or spermatids, but, with increasing dose, the effects spread to involve a wide range of spermatogenic cells including mature sperm, so that infertility could be induced very rapidly. Busulphan, however, interfered with the development of spermatogonia for several weeks, although other germinal cells were unaffected and continued to develop into mature spermatozoa. This accounted for the continuation of normal fertility for 7 weeks after a dose, before sterility suddenly developed. The antifertility activity of tretamine could be simulated by a variety of other ethyleneimino compounds, potency being greatest in trifunctional and least in monofunctional compounds. The latter were, however, very destructive to the seminiferous epithelium with increasing dose. In the rat, there appeared to be no definite relationship between the ability of alkylating substances to interfere with the activity of normal and pathological proliferating tissues, as represented by the germinal epithelium, haematopoietic, and tumour tissue. Although carcinogenicity was a biological property of alkylating agents, other chemical types of carcinogen did not interfere with fertility.In small doses, tretamine (triethylenemelamine) produces selective effects on spermatogenesis in rats, as revealed by fertility studies (Bock and Jackson, 1957). It appears that the drug can interfere with various stages of this complex process so that the sperm produced, although capable of reaching and penetrating ova, are incapable of promoting further development. Tretamine is well known for its cytotoxic effects due, it is thought, to some specific action on dividing cells. Because of its similarity to radiation, tretamine is classified as a radiomimetic drug. The present work describes the comparative actions on male rat fertility of tretamine, busulphan (Myleran), and melphalan as representative of three chemical types of alkylating radiomimetic substances. In addition the activities of a number of tri-, di-, and monofunctional ethyleneimino compounds have been examined. METHODS AND MATERIALSThe animals used were an inbred strain of Wistar rat of American origin, maintained on a standard diet provided by the Scottish N.E. Agricultural Society. The method of investigating the effect of a drug on male rat fertility has been described previously (Bock and Jackson, 1957). Briefly, it consisted of pairing treated male rats with females of established fertility, and replacing the latter at intervals of 1 week for as long as considered necessary. The date of insemination was determined by examination of a vaginal smear each morning. Because of the number of females required in each experime...

Distribution of Pyrimidine Synthetic Enzymes in the Rat Testis

“…Seminiferous tubules in treated rats consist of amorphous debris and Sertoli cells only [6]. The decline in aspartate carbamyltranferase activity is consistent with this action of Busulfan on the germinal epithelium.…”

Studies of biologically potent organotin(IV) and organosilicon(IV) complexes of a sulfur donor ligand derived from 1‐acetylferrocene

“…These results may also be correlated with the well-known fact that sulfur-containing compounds produce infertility in male rats. 36 Thus, it can be postulated that chelation through sulfur atoms induces the sterilizing activity in the biological systems.…”

Cyclophosphamide Modulates Gene Expression in Neonatal Rat Testis Following Antenatal Exposure to Fetuses During Testicular Differentiation

“…Cyclophosphamide is an alkylating agent and DNA synthesis is sensitive to the action of alkylating agents [6]. A single high-dose treatment (50-100 mg/kg) of cyclophosphamide leads to a decreased DNA and protein synthesis in spermatids [9], followed by a decrease in testicular weight [16].…”