Disease relevance of NSC 7300

• Since methoxyacetic acid has been shown to have the same spectrum of toxicity as EGME in male rats, the observed differences in the toxicological properties of EGME and PGME are thought to be due to the fact that the two materials are biotransformed via different routes to different types of metabolites [1].
• Flow cytometric (FCM) DNA content measurements were carried out on testicular monocellular suspensions obtained from mice exposed per os to a single dose of 50, 100, 300, 600, and 900 mg/kg body weight (b.w.) of 2-methoxyacetic acid (MAA) in order to investigate its cytotoxic action on germ cells [2].
• The hematopoietic toxicity of ethylene glycol monomethyl ether (EGME) and its metabolites, methoxy acetaldehyde (MALD) and methoxyacetic acid (MAA), was analyzed using human bone marrow cells from a lymphoma patient without bone marrow involvement and a human leukemia cell line, HL60 [3].

High impact information on NSC 7300

• Administration of 2-methoxyethanol to pregnant rats on day 12 of gestation induced ventral duplication of the autopod, presumably via its oxidative metabolite, methoxyacetic acid [4].
• Morphological observations indicate that the limb bud periderm is severely damaged by methoxyacetic acid so that large patches of this structure are actually missing during an extended period of limb bud development [4].
• Using a semiquantitative RT-PCR assay, messenger RNA expression was determined for each cadherin superfamily member during a postnatal developmental time-course and following ablation of specific testis cell types by ethanedimethanesulfonate, methoxyacetic acid, and 2,5-hexanedione [5].
• 2-Methoxyethanol (ME) and its metabolite, methoxyacetic acid (MAA), produce testicular lesions characterized by pachytene spermatocyte degeneration [6].
• Rat pachytene spermatocytes down-regulate a polo-like kinase and up-regulate a thiol-specific antioxidant protein, whereas sertoli cells down-regulate a phosphodiesterase and up-regulate an oxidative stress protein after exposure to methoxyethanol and methoxyacetic acid [6].

Chemical compound and disease context of NSC 7300

• The possible role of one-carbon moieties in 2-methoxyethanol and 2-methoxyacetic acid-induced developmental toxicity [7].
• The results also emphasize the role of metabolism in the testicular toxicity of glycol ethers and indicate that MAA is an active metabolite of EGM [8].

Biological context of NSC 7300

• N-acetylcysteine prevents MAA induced male germ cell apoptosis: role of glutathione and cytochrome c [9].
• Therefore, the objective of this study was to treat adult rats with methoxyacetic acid (MAA) to selectively destroy pachytene spermatocytes, examine the localization and expression of testicular clusterin, and relate this to the timing of DNA fragmentation, a hallmark of apoptosis [10].
• Alteration of the kinetics of 2-ME and its oxidation product 2-methoxyacetic acid (2-MAA), the putative ultimate toxicant, was considered [11].
• Pharmacokinetics of 2-methoxyethanol and 2-methoxyacetic acid in the pregnant mouse: a physiologically based mathematical model [12].
• The pharmacokinetic profiles of 2-methoxyacetic acid (2-MAA), the proximate toxic metabolite of 2-ME, were quantitated, generating peak concentration (Cmax) and total 2-MAA exposure values (24-hr area under the concentration-time curve; AUC) in the maternal plasma, extraembryonic fluid, and embryo [13].

Anatomical context of NSC 7300

• However, treatment of adult rats with methoxyacetic acid or hydroxyurea, which resulted in partial germ cell depletion, had no effect on total testicular AMHRII mRNA expression [14].
• Treatment of rats with MAA, which selectively depletes seminiferous tubules at most stages of pachytene spermatocytes, resulted in a marked reduction in COX II mRNA [15].
• Expression of KTT4 was not altered by ethane dimethane sulphonate-induced androgen withdrawal, but in rats treated 14 days previously with methoxyacetic acid, a marked reduction in KTT4 was noted associated with the depletion of round spermatids [16].
• Assay of methoxyacetic acid in body fluids and tissues by gas chromatography-mass spectrometry following tert.-butyldimethylsilylation [17].
• Furthermore, it appears that MAA is the proximate toxicant for ME-induced alterations in the immune system, as has been demonstrated for ME-induced reproductive and developmental toxicity [18].

Associations of NSC 7300 with other chemical compounds

• Concomitant ethanol did not affect 14C kinetics as measured in maternal blood after oral 14C-ME, but retarded ME conversion to MAA by about 2 hr [19].
• In addition, the in vitro exposure of a leukemic spleen mononuclear cell culture to 2-ME caused a dose- and time-dependent reduction in the number of leukemia cells after a single exposure to 1-100 microM concentrations, whereas the 2-ME metabolite, 2-methoxyacetic acid, was only half as effective [20].
• The mutagenicity and cytotoxicity of EGME and its major metabolites, methoxyacetaldehyde (MALD) and methoxyacetic acid (MAA) in Chinese hamster ovary (CHO) cells were therefore examined by us [21].
• We evaluated the role of tyrosine kinase pp60(c-src) in control and EGME-treated adult rat testis in vivo, as well as in vitro using cultured adult rat seminiferous tubules treated with MAA [22].
• Since glycol ethers are known to produce toxic metabolites such as the teratogenic methoxyacetic acid during biodegradation, the biological treatment of glycol ethers can be hazardous [23].

Gene context of NSC 7300

• No differences in testicular morphology or the incidence of apoptosis in the testis were seen between the cluKO and clusterin wild-type (cluWT) mice after MAA treatment [24].
• In the present study, a combination of nonradioactive in situ mRNA hybridization and immunohistochemistry was used to precisely determine the cellular expression patterns of ELP mRNA and protein in control and methoxyacetic acid (MAA)-treated rat testes [25].
• Also, methoxyacetic acid is a competitive inhibitor of sarcosine dehydrogenase with a Ki of 0.26 mM [26].
• Methoxyacetic acid administration did not affect the pattern of AR staining [27].
• Accumulation of clusterin/sulfated glycoprotein-2 in degenerating pachytene spermatocytes of adult rats treated with methoxyacetic acid [10].

Analytical, diagnostic and therapeutic context of NSC 7300

• However, Northern blot analysis showed a statistically significant increase in transferrin mRNA expression at 7 days after MAA treatment when pachytene spermatocytes were depleted from tubules at all stages of the spermatogenic cycle at which transferrin is normally expressed [28].
• Quantification of apoptotic testicular germ cells in normal and methoxyacetic acid-treated mice as determined by flow cytometry [29].
• Three days after treatment with methoxyacetic acid (MAA), many seminiferous tubules were found to lack or to have severe depletions of pachytene spermatocytes, but not of elongate spermatids [30].
• Oxidation of ME to MAA was nearly complete after 1 hr when approximately 90% of 14C in maternal plasma and conceptus coeluted with authentic 14C-MAA upon HPLC [19].
• The role of specific germ cell types in regulating the route of secretion of inhibin from the normal adult testis was studied after depletion (80-100%) of pachytene and later spermatocytes by a single oral administration of MAA (650 mg/kg) to adult rats [31].

References