Development and the environment: clues to carcinogenesis.

This commentary makes three points. First, the environment is a key determinant of developmental phenotype, with a wide variety of mechanisms that mediate this influence. Second, there is an intimate relationship between the biology of development and the biology of cancer, with many of the same signaling pathways, geneexpression profiles, endocrine and paracrine influences, and DNA modifications being involved in both. Third, althoughwe have focused extensively on the role of DNA mutation in seeking to understand the role of environment in carcinogenesis, it is perhaps time to look more widely and to apply what we know of the environmental influences on development. Since the Modern Synthesis was formulated, geneticists have dominated the argument about what determines phenotype. The answer seemed obvious: genotype determines phenotype. Other viewpoints, especially after the bizarre (and tragic) destruction of Russian genetics by Lysenko, were regarded as suspect at best, ignorant or even fraudulent at worst. Nonetheless, compelling evidence has accumulated over the 20th century: it is now clear that genotype, indeed, sets limits on the phenotype but, also, that there is marked plasticity within these limits; that many aspects of environment are key determinants of how that plasticity is further constrained; and that the influence of the environment is consistent and predictable in any given circumstance. Specific examples follow. The larvae of the moth, Nemoria arizonia, develop on oak trees: Those that hatch in spring resemble the catkins (flowers), but those that hatch in the summer look like twigs (1). The level of tannins in the diet determines the phenotype although how the signal is transduced is not yet clear. In the honeybee, a continuous diet of protein-rich royal jelly maintains the functions of the corpora allata, which produces juvenile hormones that delay metamorphosis; this, in turn, increases growth and ensures functional ovaries. This dietary regimen results in a new queen after the death of the old. The genotypes of queen and worker are the same; phenotypes differ markedly (2). The mechanism involves upregulation of energy metabolism genes (3). Folate supplementation of dams ensures that the pups of the agouti mouse (heterozygous for the VY allele of the agouti gene) are dark pigmented and slender, whereas genetically identicalmice fromunsupplementeddamsare fat and yellow (4). The mechanism involves alterations in DNA-methylation patterns (4). Alterations ofmethylation patterns also account for a higher number of glucocorticoid receptors in the hippocampus and an improved ability to respond to stress in rat pups that are maternally groomed, compared with those that are not (5, 6). When the butterfly, Araschnia levana, emerges from its pupa in spring it has a different phenotype from the genetically identical adult that emerges in summer (so different that Linnaeus classified them as different species). This difference results from changes in day length and temperature (7) and is mediated by the larval levels of ecdysone, a hormone that also controls metamorphosis (8). In mammals, sex determination is dependent on chromosomes. In many reptiles, amphibians, and fish, gonadal specification is determined by temperature (turtles and crocodilians) or social interaction (fish) and Author's Affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington; and Centre for Public Health Research, Massey University, Wellington, New Zealand