Gene expression in teratogenic exposures: A new approach to understanding individual risk

Abstract

The phenomenon of partial or incomplete penetrance is common to many paradigms of exposure to teratogens, where only some of the exposed individuals exhibit developmental defects. We here argue that the most widely used experimental approaches in reproductive toxicology do not take partial penetrance into account, and are thus likely to miss differences between affected and unaffected individuals that contribute to susceptibility for teratogenesis. We propose that focus on the variation between exposed individuals could help to discover factors that may play a causative role for abnormal developmental processes that occur with incomplete penetrance.

Effect of maternal diabetes on the embryo, fetus, and children: Congenital anomalies, genetic and epigenetic changes and developmental outcomes

“…(1) Diabetes during pregnancy increases the risk for structural birth defects in the progeny, but not all exposed individuals are affected, as a fraction of progeny can develop normally despite exposure (Ornoy et al, ; Pavlinkova et al, ; Kappen et al, ). This phenomenon of “partial penetrance” suggests that even when the exposed individuals are genetically identical (such as in an inbred strain), non‐genetic factors determine whether a given individual manifests a birth defect (Kappen and Salbaum, ). (2) The severity of defects can vary among the affected individuals, further highlighting non‐genetic differences between individuals with the same genetic background and the same exposure (unpublished data).…”

“…(4) Transcriptional profiles are altered in mouse embryos exposed to maternal diabetes during pregnancy (Pavlinkova et al, ), implicating altered regulation of gene expression, a classic epigenetic mechanism. (5) Variation between transcriptomic profiles is greater between exposed individuals (when compared to a non‐exposed control group) (Salbaum and Kappen, ; Kappen and Salbaum, ), indicating that gene regulatory mechanisms are modulated by the exposure. (6) Chromatin modifications, a subgroup of epigenetic markers, are altered by exposure to maternal diabetes and maternal obesity (Salbaum and Kappen, ), providing potential substrates in altered gene regulation.…”

“…Moreover, in the same litter of diabetic dams, significant differences in embryonic redox potential were found between malformed embryos compared to non‐malformed embryos, with the malformed embryos exhibiting reduced antioxidant capacity (Ornoy et al, 1999; Zaken et al, ). It can therefore be postulated that epigenetic differences between individuals determine the individual risk for defective neural tube closure and the extent of pathogenic development under conditions of maternal diabetes in pregnancy (Kappen and Salbaum, ).…”

Gene expression profiling of changes induced by maternal diabetes in the embryonic heart

“…Additional classes of congenital heart defects, such as thinning of the heart wall and ventricular trabeculation defects, were also detected. By way of extrapolation, we postulate that diabetic environment including hypoxic insults associated with excessive VEGF-A levels may altered morphogenic processes in the heart and, as such, Vegfa represents a candidate gene, which might trigger developmental abnormalities at the individual level and the incomplete penetrance phenotype after exposure to maternal diabetes [58].…”

Genetic, Epigenetic, and Environmental Contributions to Neural Tube Closure

“…In both a chemically induced diabetes model and a nonobese diabetic (NOD) strain, NTD-affected embryos had significantly higher variability in gene expression compared with their non-NTD littermates. Furthermore, the pathways enriched in the class of highly variable genes were different than those enriched in the differentially expressed but less-variable gene sets, suggesting a role for environmentally induced variable gene expression as a mechanism of increased NTD risk (83). Mechanistically, this may fit with recent data showing that hyperglycemia alters the epigenetic landscape.…”