Predicting developmental toxicity through toxicogenomics

Abstract

Global analysis of gene expression in target cells or tissues in response to a toxicant holds significant promise for predictive toxicology. Toxicants elicit a characteristic pattern of gene expression that is dependent on mechanism of action. These mechanism-specific transcript profiles can be used as the basis for predictive toxicology. Potential applications include prioritizing chemicals for testing and customizing testing approaches based on the chemical. Results that are useful in this predictive context can be obtained from animal or in vitro models. Gene expression analysis can also be used to elucidate the shape of the dose-response curve at exposure levels below the no observed adverse effect level, an important need in risk assessment. In this review, we will illustrate each of these points using our research on estrogen and an estrogenic mode of action as a model for how to use gene expression data in a predictive way. Although gene expression in response to estrogens is tissue, life stage, and sex specific, it is feasible to identify transcript profiles that are diagnostic of this mode of action.

Rethinking developmental toxicity testing: Evolution or revolution?

“…Common modes of action can be inferred in some cases from gene expression. For example, estrogen receptor agonism can be predicted from gene expression and other studies in vitro (Browne, Judson, Casey, Kleinstreuer, & Thomas, ; Daston & Naciff, ). Decisions can be made about a compound with suspected estrogen‐mediated toxicity without whole‐animal testing, at least with regard to modes of action for which estrogen receptor agonism is a key event and with regard to potency/efficacy considerations.…”

Gene–Environment Interactions

“…Studies in rats showed correlation with human toxicity reflected in gene-expression changes in peripheral blood cells (Bushel et al, 2007). The same approach has been applied to developmental toxicity (Daston and Naciff, 2010). Another approach is to compare profiles of differential gene expression in target and non-target organs, illustrated with methapyrilene (Auman et al, 2007).…”

Commentary on the Role of Maternal Toxicity on Developmental Toxicity

“…), are the major reasons (along with increased software sophistication) for the increased interest in the development, performance, analyses, and interpretation of increasingly large and sophisticated in vitro and in silico tests/assays, and for increased usage of such evaluations. The in vitro tests typically involve undifferentiated or differentiating embryonic stem cells (human, other mammalian species) in culture exposed to the chemical under test looking at gene expression profiling (Van Dartel et al, ), explanted whole embryo culture, cultured embryonic limb buds, brain regions, differentiating embryonic organs in micromass cultures, stem cell embryoid bodies in hanging drop culture, all mammalian in origin (e.g., Chapin et al, ; Van Dartel et al, ), toxicogenomics (e.g., Daston and Naciff, ), and increasing usage of developing non‐mammalian (non‐placental) vertebrates (such as the Zebrafish; e.g., Chapin et al, ; McCollum et al, ; Oggier et al, ) and invertebrates (such as molluscs). The pharmaceutical industry has used these early in vitro “toxicity” screens for many years to help select the best lead drugs early on for further development; they still do the in vivo testing later, but on the short list of the most promising candidates.…”