Strain Differences in Developmental Vulnerability to Alcohol Exposure via Embryo Culture in Mice

Yuanyuan Chen, Nail Can Ozturk, Lijun Ni, Charles Goodlett, Feng Zhou

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Background: Prenatal alcohol exposure can result in varying degrees of neurodevelopmental deficits, growth retardation, and facial dysmorphology. Variation in these adverse outcomes not only depends on the dose and pattern of alcohol exposure but also on less well understood interactions among environmental, genetic, and maternal factors. The current study tested the hypothesis that fetal genotype is an important determinant of ethanol teratogenesis by evaluating effects of ethanol exposure via embryo culture in 3 inbred strains of mice known to differ in the vulnerability of prenatal alcohol exposure in vivo. Methods: Three strains of mice, C57BL/6N (B6), DBA/2 (D2), and 129S6/SvEvTac (129S6) were assessed in a whole embryo culture beginning on embryonic day 8.25, with or without alcohol administration at 88mM for 6hours followed by 42hours culture in ethanol-free media. Results: Contrasting strain differences in susceptibility were observed for the brain, the face, and other organ systems using the Maele-Fabry and Picard scoring system. The forebrain, midbrain, hindbrain, heart, optic vesicle, caudal neural tube, and hindlimbs of the B6 mice were severely delayed in growth, whereas compared to the respective controls, only the forebrain and optic vesicle were delayed in the D2 mice, and no effects were found in the 129S6 mice. A large number of cleaved (c)-caspase 3 positive (+) cells were found in regions of the brain, optic vesicles, cranial nerve nuclei V, VII, VIII, and IX as well as the craniofacial primordial; only a few were found in corresponding regions of the B6 controls. In contrast, only a small number of c-caspase 3 immunostaining cells were found in either the alcohol treated or the controls of the D2 embryos and in 129S6 embryos. The independent apoptotic markers TUNEL and Nile blue staining further confirmed the strain differences in apoptotic responses in both the neural tube and craniofacial primordia. Conclusions: Under embryo culture conditions, in which alcohol exposure factors and fetal developmental staging were controlled, and maternal and intrauterine factors were eliminated, the degree of growth retardation and the extent and type of neurodevelopmental teratogenesis varied significantly across strains. Notably, the 129S6 strain was remarkably resistant to alcohol-induced growth deficits, confirming a previous in vivo study, and the D2 strain was also significantly less affected than the B6 strain. These findings demonstrate that fetal genotype is an important factor that can contribute to the variation in fetal alcohol spectrum disorder.

Original languageEnglish
Pages (from-to)1293-1304
Number of pages12
JournalAlcoholism: Clinical and Experimental Research
Volume35
Issue number7
DOIs
StatePublished - Jul 2011

Fingerprint

Embryonic Structures
Alcohols
Teratogenesis
Neural Tube
Ethanol
Optics
Growth
Prosencephalon
Caspase 3
Genotype
Brain
Mothers
Fetal Alcohol Spectrum Disorders
Inbred DBA Mouse
Rhombencephalon
Inbred Strains Mice
Trigeminal Nerve
In Situ Nick-End Labeling
Hindlimb
Mesencephalon

Keywords

  • Apoptosis
  • Embryo Culture
  • Fetal Alcohol Syndrome
  • Mouse Inbred Strains

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Psychiatry and Mental health
  • Toxicology

Cite this

Strain Differences in Developmental Vulnerability to Alcohol Exposure via Embryo Culture in Mice. / Chen, Yuanyuan; Ozturk, Nail Can; Ni, Lijun; Goodlett, Charles; Zhou, Feng.

In: Alcoholism: Clinical and Experimental Research, Vol. 35, No. 7, 07.2011, p. 1293-1304.

Research output: Contribution to journalArticle

Chen, Yuanyuan ; Ozturk, Nail Can ; Ni, Lijun ; Goodlett, Charles ; Zhou, Feng. / Strain Differences in Developmental Vulnerability to Alcohol Exposure via Embryo Culture in Mice. In: Alcoholism: Clinical and Experimental Research. 2011 ; Vol. 35, No. 7. pp. 1293-1304.
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N2 - Background: Prenatal alcohol exposure can result in varying degrees of neurodevelopmental deficits, growth retardation, and facial dysmorphology. Variation in these adverse outcomes not only depends on the dose and pattern of alcohol exposure but also on less well understood interactions among environmental, genetic, and maternal factors. The current study tested the hypothesis that fetal genotype is an important determinant of ethanol teratogenesis by evaluating effects of ethanol exposure via embryo culture in 3 inbred strains of mice known to differ in the vulnerability of prenatal alcohol exposure in vivo. Methods: Three strains of mice, C57BL/6N (B6), DBA/2 (D2), and 129S6/SvEvTac (129S6) were assessed in a whole embryo culture beginning on embryonic day 8.25, with or without alcohol administration at 88mM for 6hours followed by 42hours culture in ethanol-free media. Results: Contrasting strain differences in susceptibility were observed for the brain, the face, and other organ systems using the Maele-Fabry and Picard scoring system. The forebrain, midbrain, hindbrain, heart, optic vesicle, caudal neural tube, and hindlimbs of the B6 mice were severely delayed in growth, whereas compared to the respective controls, only the forebrain and optic vesicle were delayed in the D2 mice, and no effects were found in the 129S6 mice. A large number of cleaved (c)-caspase 3 positive (+) cells were found in regions of the brain, optic vesicles, cranial nerve nuclei V, VII, VIII, and IX as well as the craniofacial primordial; only a few were found in corresponding regions of the B6 controls. In contrast, only a small number of c-caspase 3 immunostaining cells were found in either the alcohol treated or the controls of the D2 embryos and in 129S6 embryos. The independent apoptotic markers TUNEL and Nile blue staining further confirmed the strain differences in apoptotic responses in both the neural tube and craniofacial primordia. Conclusions: Under embryo culture conditions, in which alcohol exposure factors and fetal developmental staging were controlled, and maternal and intrauterine factors were eliminated, the degree of growth retardation and the extent and type of neurodevelopmental teratogenesis varied significantly across strains. Notably, the 129S6 strain was remarkably resistant to alcohol-induced growth deficits, confirming a previous in vivo study, and the D2 strain was also significantly less affected than the B6 strain. These findings demonstrate that fetal genotype is an important factor that can contribute to the variation in fetal alcohol spectrum disorder.

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