Effect of ethylene glycol monomethyl ether on spermatogenesis, dominant lethality, and F₁ abnormalities in the rat and the mouse after treatment of F₀ males

Abstract

Adult male CD rats and CD-1 mice were given a single oral dose of ethylene glycol monomethyl ether (EGM) at 0, 500, 750, 1,000, or 1500 mg/kg. Groups of 10 were killed at weekly intervals after dosing for analysis of sperm counts and morphology or testicular histology; further groups of 10 were sequentially mated to pairs of virgin females to test for dominant lethality or gross foetal malformations in the F1 generation (F1 abnormalities). EGM was found to deplete the spermatocytes of both species severely, principally pachytene cells, but with other stages affected with increasing dose. A delay in the progression of spermatogenesis may account for a discrepancy between the apparent stage-specificity of damage deduced from lowered sperm counts and that observed histologically. In the rat, morphological abnormalities were observed in sperm that had been exposed as spermatocytes; in the mouse, however, the sensitive cells were the late spermatocytes and early spermatids. In all these parameters there was an indication of a dose-response relationship in both rats and mice. In the mating studies EGM induced a dose-related decrease in fertility 5 weeks after dosing in the rat, but complete sterility in all but the lowest dose after 6 weeks. In contrast, EGM had no effect on the reproductive capacity of the mouse. There was no statistically significant evidence for the induction of dominant lethal mutations or F1 abnormalities in either species. A single oral dose of cyclophosphamide (CTX) at 100 mg/kg induced a significant increase in dominant lethality in both species. CTX reduced the number of total implants in the rat and induced a nonsignificant increase in the number of abnormal offspring sired by treated male mice.

Review Article: Evaluation of Testicular Toxicity in Safety Evaluation Studies: The Appropriate Use of Spermatogenic Staging

“…5). However, if the dose level is raised further (750 mg/kg/day), spermatids and spermatogonia are also affected (2).…”

A Time-Course Characterization of Male Reproductive Toxicity in Rats Treated With Methyl Methanesulphonate (Mms)

“…There are several compounds that have already been identified as cellular targets for the induction of sperm morphological abnormalities, such as ethylene glycol monomethyl ether (EGME) for spermatocytes (Anderson et al, 1987); boric acid for mid spermatid (Linder et al, 1990); dibromo acetic acid (DBAA) for late and/or elongating spermatid (Linder et al, 1994). Although the terminology employed in each study was different, substantially the same finding of "tailless sperm" has been consistently observed as a major finding among the studies, such as EGME, separated heads (Anderson et al, 1987); boric acid, decapitation and no head (Linder et al, 1990;Yoshizaki et al, 1999); DBAA, isolated heads (Tsuchiya et al, 2000). Since the tailless sperm have been detected in the sperm morphological examination regardless of the cellular target, it can be suggested that the tailless sperm counting is a robust measure in the sperm morphological examination for the detection of spermatotoxicity.…”

2‐Methoxyethanol [MAK Value Documentation in German language, 2009]

“…Die hohen Dosierungen wirkten zytotoxisch im Knochenmark (Au et al 1996). Aus drei publizierten Dominant-Letal-Tests (Anderson et al 1987;McGregor et al 1983;Rao et al 1983) an Nagern ergeben sich keine eindeutigen Hinweise auf die Induktion von dominanten Letalmutationen, da die beobachteten Präimplantationsver-luste vermutlich auf die spermatotoxische Wirkung des 2-Methoxyethanol zurückzu-führen sind (BUA 1997). Ein erhöhter Postimplantationsverlust wurde bei CD-Ratten nach einmaliger oraler Gabe von 500, 750, 1000 bzw.…”