Multilevel complex interactions between genetic, epigenetic and environmental factors in the aetiology of anomalies of dental development.

Dental anomalies are caused by complex interactions between genetic, epigenetic and environmental factors during the long process of dental development. This process is multifactorial, multilevel, multidimensional and progressive over time. In this paper the evidence from animal models and from human studies is integrated to outline the current position and to construct and evaluate models, as a basis for future work. Dental development is multilevel entailing molecular and cellular interactions which have macroscopic outcomes. It is multidimensional, requiring developments in the three spatial dimensions and the fourth dimension of time. It is progressive, occurring over a long period, yet with critical stages. The series of interactions involving multiple genetic signalling pathways are also influenced by extracellular factors. Interactions, gradients and spatial field effects of multiple genes, epigenetic and environmental factors all influence the development of individual teeth, groups of teeth and the dentition as a whole. The macroscopic, clinically visible result in humans is a complex unit of four different tooth types formed in morphogenetic fields, in which teeth within each field form directionally and erupt at different times, reflecting the spatio-temporal control of development. Even when a specific mutation of a single gene or one major environmental insult has been identified in a patient with a dental anomaly, detailed investigation of the phenotype often reveals variation between affected individuals in the same family, between dentitions in the same individual and even between different teeth in the same dentition. The same, or closely similar phenotypes, whether anomalies of tooth number or structure, may arise from different aetiologies: not only mutations in different genes but also environmental factors may result in similar phenotypes. Related to the action of a number of the developmental regulatory genes active in odontogenesis, in different tissues, mutations can result in syndromes of which dental anomalies are part. Disruption of the antagonistic balance between developmental regulatory genes, acting as activators or inhibitors can result in dental anomalies. There are critical stages in the development of the individual tooth germs and, if progression fails, the germ will not develop further or undergoes apoptosis. The reiterative signalling patterns over time during the sequential process of initiation and morphogenesis are reflected in the clinical association of anomalies of number, size and form and the proposed models. An initial step in future studies is to combine the genetic investigations with accurate recording and measurement of the phenotype. They also need to collate findings at each level and exploit the accurate definition of both human and murine phenotypes now possible.