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Developmental phase alters dosimetry-teratogenicity relationship for 2-methoxyethanol in CD-1 mice.
Teratology. 1994 Mar; 49(3):218-27.T

Abstract

The industrial solvent 2-methoxyethanol (2-ME) elicits phase-specific terata in mice through its primary metabolite and proximate toxicant, 2-methoxyacetic acid (2-MAA). Recent pharmacokinetic studies indicate that the incidence and severity of digit malformations induced in CD-1 mice by 2-ME exposure on gestation day (gd) 11 (copulation plug = gd 0) correlate better with the total 2-MAA exposure over time (= area under the curve; AUC) than with its peak concentrations (Cmax) in maternal plasma, embryo and extraembryonic fluid. In this study, the phase specificity of exencephaly induction by 2-ME was investigated to ascertain whether the 2-ME/2-MAA dosimetry-teratogenicity relationship remains consistent throughout organogenesis. Following a single intravenous (iv) bolus dose of 250 mg 2-ME/kg given to pregnant mice, exposure on gd 8 was decidedly the gestation day that best balanced low embryo lethality and high malformation incidence as recorded in near-term fetuses. Concentrations of 2-MAA were measured during distribution and elimination in maternal plasma and conceptuses following iv bolus doses of 175, 250, and 325 mg 2-ME/kg, as well as during and after termination of subcutaneous (sc) constant-rate infusion (4, 6, and 8 hr; 8 microliters/hr) of 277, 392, and 606 mg 2-ME/kg total doses. For all administration regimens, exencephaly incidence rates were determined in fetuses on gd 18. Similar plasma 2-MAA Cmax values (approximately 5 mmol/l) and fetal malformation frequencies (approximately 12%) were induced by sc infusion of 392 mg 2-ME/kg or a bolus dose of 250 mg 2-ME/kg. However, the AUC produced by infusion was significantly larger than that following the iv bolus dose (38 vs. 26 mmol.hr/l, respectively). In both maternal plasma and conceptuses, the correlation coefficients between Cmax and exencephaly rates, as well as developmental toxicity, were higher than they were for AUC and those end points. This outcome suggests that dosimetry-teratogenicity determinants may be quite specific for a distinct developmental phase during which a particular organ differentiates and a specific chemical acts upon the embryo.

Authors+Show Affiliations

Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 22709.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

8059429

Citation

Terry, K K., et al. "Developmental Phase Alters Dosimetry-teratogenicity Relationship for 2-methoxyethanol in CD-1 Mice." Teratology, vol. 49, no. 3, 1994, pp. 218-27.
Terry KK, Elswick BA, Stedman DB, et al. Developmental phase alters dosimetry-teratogenicity relationship for 2-methoxyethanol in CD-1 mice. Teratology. 1994;49(3):218-27.
Terry, K. K., Elswick, B. A., Stedman, D. B., & Welsch, F. (1994). Developmental phase alters dosimetry-teratogenicity relationship for 2-methoxyethanol in CD-1 mice. Teratology, 49(3), 218-27.
Terry KK, et al. Developmental Phase Alters Dosimetry-teratogenicity Relationship for 2-methoxyethanol in CD-1 Mice. Teratology. 1994;49(3):218-27. PubMed PMID: 8059429.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Developmental phase alters dosimetry-teratogenicity relationship for 2-methoxyethanol in CD-1 mice. AU - Terry,K K, AU - Elswick,B A, AU - Stedman,D B, AU - Welsch,F, PY - 1994/3/1/pubmed PY - 1994/3/1/medline PY - 1994/3/1/entrez SP - 218 EP - 27 JF - Teratology JO - Teratology VL - 49 IS - 3 N2 - The industrial solvent 2-methoxyethanol (2-ME) elicits phase-specific terata in mice through its primary metabolite and proximate toxicant, 2-methoxyacetic acid (2-MAA). Recent pharmacokinetic studies indicate that the incidence and severity of digit malformations induced in CD-1 mice by 2-ME exposure on gestation day (gd) 11 (copulation plug = gd 0) correlate better with the total 2-MAA exposure over time (= area under the curve; AUC) than with its peak concentrations (Cmax) in maternal plasma, embryo and extraembryonic fluid. In this study, the phase specificity of exencephaly induction by 2-ME was investigated to ascertain whether the 2-ME/2-MAA dosimetry-teratogenicity relationship remains consistent throughout organogenesis. Following a single intravenous (iv) bolus dose of 250 mg 2-ME/kg given to pregnant mice, exposure on gd 8 was decidedly the gestation day that best balanced low embryo lethality and high malformation incidence as recorded in near-term fetuses. Concentrations of 2-MAA were measured during distribution and elimination in maternal plasma and conceptuses following iv bolus doses of 175, 250, and 325 mg 2-ME/kg, as well as during and after termination of subcutaneous (sc) constant-rate infusion (4, 6, and 8 hr; 8 microliters/hr) of 277, 392, and 606 mg 2-ME/kg total doses. For all administration regimens, exencephaly incidence rates were determined in fetuses on gd 18. Similar plasma 2-MAA Cmax values (approximately 5 mmol/l) and fetal malformation frequencies (approximately 12%) were induced by sc infusion of 392 mg 2-ME/kg or a bolus dose of 250 mg 2-ME/kg. However, the AUC produced by infusion was significantly larger than that following the iv bolus dose (38 vs. 26 mmol.hr/l, respectively). In both maternal plasma and conceptuses, the correlation coefficients between Cmax and exencephaly rates, as well as developmental toxicity, were higher than they were for AUC and those end points. This outcome suggests that dosimetry-teratogenicity determinants may be quite specific for a distinct developmental phase during which a particular organ differentiates and a specific chemical acts upon the embryo. SN - 0040-3709 UR - https://www.unboundmedicine.com/medline/citation/8059429/Developmental_phase_alters_dosimetry_teratogenicity_relationship_for_2_methoxyethanol_in_CD_1_mice_ L2 - https://doi.org/10.1002/tera.1420490318 DB - PRIME DP - Unbound Medicine ER -