Effects of Ethylene Glycol Monomethyl Ether and Its Metabolite, 2‐Methoxyacetic Acid, on Organogenesis Stage Mouse Limbs In Vitro. (2nd May 2014)

• Record Type: Journal Article
• Authors: Dayan, Caroline; Hales, Barbara F.
• Is Part Of: Birth defects research. Volume 101:Number 3(2014)
• Page Start: 254
• Page End: 261
• Publication Date: 2014-05-02
• Subjects: Developmental toxicology -- Periodicals; Reproductive toxicology -- Periodicals; 616.65071
• DOI: 10.1002/bdrb.21108
• Languages: English
• ISSNs: 1542-9733

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Exposure to ethylene glycol monomethyl ether (EGME), a glycol ether compound found in numerous industrial products, or to its active metabolite, 2‐methoxyacetic acid (2‐MAA), increases the incidence of developmental defects. Using an in vitro limb bud culture system, we tested the hypothesis that the effects of EGME on limb development are mediated by 2‐MAA‐induced alterations in acetylation programming. Murine gestation day 12 embryonic forelimbs were exposed to 3, 10, or 30 mM EGME or 2‐MAA in culture for 6 days to examine effects on limb morphology; limbs were cultured for 1 to 24 hr to monitor effects on the acetylation of histones (H3K9 and H4K12), a nonhistone protein, p53 (p53K379), and markers for cell cycle arrest (<italic>p21</italic>) and apoptosis (cleaved caspase‐3). EGME had little effect on limb morphology and no significant effects on the acetylation of histones or p53 or on biomarkers for cell cycle arrest or apoptosis. In contrast, 2‐MAA exposure resulted in a significant concentration‐dependent increase in limb abnormalities. 2‐MAA induced the hyperacetylation of histones H3K9Ac and H4K12Ac at all concentrations tested (3, 10, and 30 mM). Exposure to 10 or 30 mM 2‐MAA significantly increased acetylation of p53 at K379, <italic>p21</italic> expression, and caspase‐3 cleavage. Thus, 2‐MAA, the proximate metabolite of EGME, disrupts limb development in vitro, modifies acetylation programming, and induces biomarkers of cell cycle arrest and apoptosis</p> </abstract>