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Review
. 2020 Nov;112(19):1660-1698.
doi: 10.1002/bdr2.1830. Epub 2020 Oct 30.

Environmental mechanisms of orofacial clefts

Michael A Garland  1   2 , Kurt Reynolds  1   2   3 , Chengji J Zhou  1   2   3
Affiliations
Review

Environmental mechanisms of orofacial clefts

Michael A Garland et al. Birth Defects Res. 2020 Nov.

Abstract

Orofacial clefts (OFCs) are among the most common birth defects and impart a significant burden on afflicted individuals and their families. It is increasingly understood that many nonsyndromic OFCs are a consequence of extrinsic factors, genetic susceptibilities, and interactions of the two. Therefore, understanding the environmental mechanisms of OFCs is important in the prevention of future cases. This review examines the molecular mechanisms associated with environmental factors that either protect against or increase the risk of OFCs. We focus on essential metabolic pathways, environmental signaling mechanisms, detoxification pathways, behavioral risk factors, and biological hazards that may disrupt orofacial development.

Keywords: behavioral exposure; drinking alcohol; environmental signaling pathways; folate; occupational exposure; orofacial clefts; pathogenic factors; retinoid acid; smoking tobacco.

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Conflict of interest statement

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

Figures

Figure 1.
Figure 1.
Simplified retinoic acid receptor (RAR) signaling pathway. The pathway’s modulation of gene expression and protein abundance associated with orofacial clefts is shown in the white box. CRABP, cellular retinoic acid binding protein. RARE, retinoic acid receptor response element. RXR, retinoid X receptor.
Figure 2.
Figure 2.
Simplified aryl hydrocarbon receptor (AHR) signaling pathway. Representative members of ligand classes are presented in the top panels, while the AHR transcriptional activation pathway is illustrated below. The pathway’s modulation of gene expression and protein abundance associated with orofacial clefts is shown in the white box. ARNT, aryl hydrocarbon receptor nuclear translocator. AHRR, aryl hydrocarbon receptor repressor. AIP, aryl hydrocarbon receptor interacting protein. DRE, dioxin response element. PAH, polycyclic aromatic hydrocarbon. PCB, polychlorinated biphenyl. PCDF, polychlorinated dibenzofuran.
Figure 3.
Figure 3.
Simplified glucocorticoid receptor (GR) signaling pathway. Examples of the endogenous ligand (cortisol) and a synthetic ligand (dexamethasone) are presented in the top panels. The pathway’s direct or indirect modulation of gene expression and protein abundance associated with orofacial clefts is shown in the white box. FKBP51, FK506 binding protein 51 (representing immunophilins). GRE, glucocorticoid response element. HSP90, heat shock protein 90.
See this image and copyright information in PMC

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