Genotoxicants Target Distinct Molecular Networks in Neonatal Neurons

BACKGROUND: Exposure of the brain to environmental agents during critical periods of neuronal development is considered a key factor underlying many neurologic disorders. OBJECTIVES: In this study we examined the influence of genotoxicants on cerebellar function during early development by measuring global gene expression changes. METHODS: We measured global gene expression in immature cerebellar neurons (i.e., granule cells) after treatment with two distinct alkylating agents, methylazoxymethanol (MAM) and nitrogen mustard (HN2). Granule cell cultures were treated for 24 hr with MAM (10–1,000 μM) or HN2 (0.1–20 μM) and examined for cell viability, DNA damage, and markers of apoptosis. RESULTS: Neuronal viability was significantly reduced (p < 0.01) at concentrations > 500 μM for MAM and > 1.0 μM for HN2; this correlated with an increase in both DNA damage and markers of apoptosis. Neuronal cultures treated with sublethal concentrations of MAM (100 μM) or HN2 (1.0 μM) were then examined for gene expression using large-scale mouse cDNA microarrays (27,648). Gene expression results revealed that a) global gene expression was predominantly up-regulated by both genotoxicants; b) the number of down-regulated genes was approximately 3-fold greater for HN2 than for MAM; and c) distinct classes of molecules were influenced by MAM (i.e, neuronal differentiation, the stress and immune response, and signal transduction) and HN2 (i.e, protein synthesis and apoptosis). CONCLUSIONS: These studies demonstrate that individual genotoxicants induce distinct gene expression signatures. Further study of these molecular networks may explain the variable response of the developing brain to different types of environmental genotoxicants

Correlated contemporary evolution of life history traits in New Zealand Chinook salmon, Oncorhynchus tshawytscha

Size at age and age at maturity are important life history traits, affecting individual fitness and population demography. In salmon and other organisms, size and growth rate are commonly considered cues for maturation and thus age at maturity may or may not evolve independently of these features. Recent concerns surrounding the potential phenotypic and demographic responses of populations facing anthropogenic disturbances, such as climate change and harvest, place a premium on understanding the evolutionary genetic basis for evolution in size at age and age at maturity. In this study, we present the findings from a set of common-garden rearing experiments that empirically assess the heritable basis of phenotypic divergence in size at age and age at maturity in Chinook salmon (Oncorhynchus tshawytscha) populations introduced to New Zealand. We found consistent evidence of heritable differences among populations in both size at age and age at maturity, often corresponding to patterns observed in the wild. Populations diverged in size and growth profiles, even when accounting for eventual age at maturation. By contrast, most, but not all, cases of divergence in age at maturity were driven by the differences in size or growth rate rather than differences in the threshold relationship linking growth rate and probability of maturation. These findings help us understand how life histories may evolve through trait interactions in populations exposed to natural and anthropogenic disturbances, and how we might best detect such evolution