Specific organic aliphatic monocarboxylic acids (or their anions), such as the anticonvulsant valproic acid or the metabolites of environmental contaminants, 2-methoxyacetic acid and 2- ethylhexanoic acid, are teratogenic in more than a single species. These agents cause a wide variety of types of malformations depending on the gestational time at which the agent is administered. After determining that the embryonic intracellular pH (pHi) is increased following the administration of a teratogenic dose of 2-ethylhexanoic or valproic acid, but unchanged after a higher but non-teratogenic dose of 2-ethylhexanoic or valproic acid, but unchanged after a higher but non-teratogenic dose of the naturally occurring fatty acid, 1-octanoic acid, a hypothesis was formulated. The hypothesis was that increases in embryonic pHi were the mechanism of action by which the monocarboxylates induce congential malformations. This study will specifically analyzee the relationship of neural tube defects to increases in pHi because these agents are known to produce strain specific neural tube defects in vivo, the failure of neural tube closure can be readily detected in whole embryo culture, and valproic acid is a suspected human neural tube teratogen. The basic hypothesis will be analyzed from three perspectives. First, the strength of the association between neural tube teratogenicity and increased embryonic pHi will be determined by evaluating these parameters in teratogenic and non-teratogenic monocarboxylic acids. The association will also be evaluated via the use of inbred strains of mice, one of which has been found to be susceptibel to valproic acid-induced neural tube teratogenesis (SWV) while the other has been shown to be resistant (C57BL/6). Second, the mechanism by which the organic acids cause and increase in embryonic pHi will be explored. These studies will focus on the inhibition of three membrane transport processes which may be involved in the regulation of embryonic pHi, specifically, the Na+/H+ antiporter, the monocarboxylate/transporter, and the C1-/HCO3- exchanger. Third, this proposal will explore several hypothesized biochemical pathways by which the increase in embryonic pHi may cuase defects. Analysis of one of these pathways suggests that an increase in glycolytic flux causes an increase in lactate which is teratogenic. Analysis of a second pathway suggests that an increase in glycolytic flux causes an increase in lactate which is teratogenic. Analysis of a second pathway suggests that the activation of Na+/K+ ATPase usurps the embryonic ATP supply inducing malformations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29ES004402-02
Application #
3465179
Study Section
Human Embryology and Development Subcommittee 2 (HED)
Project Start
1987-07-01
Project End
1992-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Scott Jr, W J; Walter, R; Tzimas, G et al. (1994) Endogenous status of retinoids and their cytosolic binding proteins in limb buds of chick vs mouse embryos. Dev Biol 165:397-409
Scott Jr, W J; Collins, M D; Nau, H (1994) Pharmacokinetic determinants of embryotoxicity in rats associated with organic acids. Environ Health Perspect 102 Suppl 11:97-101
Scott, W J; Collins, M D; Ernst, A N et al. (1994) Enhanced expression of limb malformations and axial skeleton alterations in legless mutants by transplacental exposure to retinoic acid. Dev Biol 164:277-89
Scott, W J; Collins, M D; Ernst, A N et al. (1993) Exacerbation of limb malformations in legless (lgl) homozygotes by retinoic acid (RA). Prog Clin Biol Res 383B:735-8
Collins, M D; Scott, W J; Miller, S J et al. (1992) Murine teratology and pharmacokinetics of the enantiomers of sodium 2-ethylhexanoate. Toxicol Appl Pharmacol 112:257-65
Collins, M D; Walling, K M; Resnick, E et al. (1991) The effect of administration time on malformations induced by three anticonvulsant agents in C57BL/6J mice with emphasis on forelimb ectrodactyly. Teratology 44:617-27
Srivastava, M; Collins, M D; Scott Jr, W J et al. (1991) Transplacental distribution of weak acids in mice: accumulation in compartments of high pH. Teratology 43:325-9
Zimmerman, E F; Scott Jr, W J; Collins, M D (1990) Ethanol-induced limb defects in mice: effect of strain and Ro15-4513. Teratology 41:453-62
Scott, W J; Duggan, C A; Schreiner, C M et al. (1990) Reduction of embryonic intracellular pH: a potential mechanism of acetazolamide-induced limb malformations. Toxicol Appl Pharmacol 103:238-54
Zimmerman, E F; Collins, M (1989) Chloride transport in embryonic cells: effect of ethanol and GABA. Teratology 40:593-601

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