Efcab7 deletion sensitizes mice to the teratogenic effects of gastrulation-stage alcohol exposure

• Published in: Reproductive toxicology (Elmsford, N.Y.) N.Y.), 2024-12, Vol.130, p.108729, Article 108729
• Main Authors: Fish, Eric W., Boschen, Karen E., Parnell, Scott E.
• Format: Article
• Language: English
• Subjects: Anilides - toxicity; Animals; Anophthalmia; Craniofacial Abnormalities - chemically induced; Craniofacial Abnormalities - genetics; Cyclohexylamines - toxicity; Ethanol; Ethanol - toxicity; Female; Fetal alcohol syndrome; Gastrulation - drug effects; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; Holoprosencephaly; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Pregnancy; Primary cilia; Pyridines - toxicity; Smoothened Receptor - genetics; Teratogens - toxicity
• ISSN: 0890-6238; 1873-1708; 1873-1708
• DOI: 10.1016/j.reprotox.2024.108729

Alcohol exposure during the gastrulation stage of development can disrupt Sonic hedgehog (Shh) signaling and cause eye, craniofacial, and brain defects. One of the genes that regulates Shh signaling is Efcab7, which encodes a protein that facilitates the actions of Smoothened (Smo), a critical component of the Shh pathway. Previous work from our lab has demonstrated that Efcab7 is differentially expressed between two sub-strains of C57BL/6 mice that differ in their sensitivity to gastrulation-stage alcohol exposure. The more alcohol-sensitive C57BL/6 J mice express lower levels of Efcab7 during gastrulation than do the less alcohol-sensitive C57BL/6NHsd mice. The current study examined whether partial or full Efcab7 deletions render mice more sensitive to gastrulation-stage alcohol exposure and affect the sensitivity to other modulators of Shh signaling that cause craniofacial malformations. Efcab7+/- dams were mated with Efcab7+/- sires to produce Efcab7+/+, Efcab7+/-, and Efcab7-/- fetuses. On gestational day 7 (GD 7), they received either alcohol (two doses of 2.9 g/kg, i.p., given 4 hours apart), the Smo antagonist vismodegib (40 mg/kg, or vehicle, p.o.), the Smo agonist SAG (20 mg/kg) or the appropriate vehicles. GD 17 fetuses were collected and examined for ocular and craniofacial dysmorphology. As compared to Efcab7+/+ fetuses, Efcab7-/- fetuses exposed to alcohol or vismodegib treatment had more severe ocular and craniofacial malformations. In contrast, Efcab7-/- fetuses had less severe malformations induced by SAG. These results confirm that Efcab7 can modify responses to Shh agonists and antagonists and further identify Efcab7 as a gene important for the sensitivity to gastrulation-stage alcohol exposure. •Fetal mice lacking the Efcab7 gene have no overt developmental defects.•Mice lacking the Efcab7 gene have more severe eye, face, and brain defects following a gastrulation-stage alcohol exposure.•Mice lacking the Efcab7 gene are less severely affected by a Smoothened agonist and more affected by a Smoothened antagonist.