Journal
ENVIRONMENTAL HEALTH PERSPECTIVES
Volume 119, Issue 11, Pages 1590-1595Publisher
US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE
DOI: 10.1289/ehp.1003075
Keywords
AHR; cleft; mesenchyme; mouse; nasal epithelium; RAR; retinaldehyde dehydrogenase (RALDH); teratogenesis; 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)
Funding
- Centre National de la Recherche Scientifique
- Institut National de la Sante et de la Recherche Medicale
- Hopital Universitaire de Strasbourg
- French Ministry of Research
- EU-funded BoneTox Network [QLK-CT-2002-02528]
Ask authors/readers for more resources
BACKGROUND: Palate development depends on complex events and is very sensitive to disruption. Accordingly, clefts are the most common congenital malformations worldwide, and a connection is proposed with fetal exposure to toxic factors or environmental contaminants, such as dioxins. There is increasing evidence that dioxin interferes with all-trans-retinoic acid (atRA), a hormone-like signal derived from vitamin A, which plays an essential role during embryonic development. Although similarities have been described between dioxin-induced toxicity and the outcome of altered atRA signaling during palate development, their relationship needs to be clarified. OBJECTIVES: We used a genetic approach to understand the interaction between atRA and dioxin and to identify the cell type targeted by dioxin toxicity during secondary palate formation in mice. METHODS: We analyzed the phenotype of mouse embryos harboring an atRA-sensitive reporter transgene or bearing null mutations for atRA-synthesizing enzymes (RALDH) or atRA receptors (RAR) and maternally exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at gestation day 10.5. RESULTS: We found that an intact atRA signal was required to enable TCDD to induce cleft palate. This mandatory atRA signal was generated through the activity of RALDH3 in the nasal epithelium and was transduced by RAR gamma (RARG) in the nasal mesenchyme, where it notably controlled aryl hydrocarbon receptor (Ahr) transcript levels. TCDD also did not alter the developmental pattern of atRA signaling during palate formation. CONCLUSIONS: TCDD-induced alteration of secondary palate development in the mouse appears to depend on atRA signaling, which controls AHR expression. This mechanism is likely conserved throughout vertebrate evolution and may therefore be relevant in humans.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available