Enhancement of developmental toxicity effects of chemicals by gestational stress. A review

Risk assessment of developmental toxicants is almost exclusively based on single chemicals studied in animals under controlled experimental conditions, as to reduce stress. Although humans may be exposed simultaneously to numerous hazards, little is known about the interaction of prenatal chemical exposures with other factors, such as maternal stress, itself a modifier of fetal development. Gestational stress has been hypothesized to enhance the developmental toxicity of chemicals. This review identified 36 animal studies investigating if maternal stress may enhance the effects of prenatal chemical exposure, and evaluated the presented hypothesis. Studies of a broad range of chemicals and developmental endpoints support the notion, that maternal stress is able to enhance the effects of developmental toxicants, although stress mitigated chemically induced effects in a few cases. Maternal stress most often enhanced chemical developmental toxicity at dose levels associated with severe maternal toxicity or where test agents were already above threshold for effect. Thus, LOAEL(chemical) was generally similar to LOAEL(chemical+stress), although not necessarily for the same endpoint. It should be noted that the database contained a limited number of studies, and only a single high dose level was applied in most studies, rendering establishment of NOAELs for combined exposures impossible. Furthermore, for some compounds, the margin between human exposure levels and the LOAEL(chemical+stress) seems small. Future studies are recommended to investigate compounds, for which maternal stress was already proven as an enhancer, at lower dose levels. Interactive response seems to depend on stressor severity and timing of chemical exposure relative to maternal stress which should be further scrutinized.