Systems toxicology studies reveal important insights about chronic exposure of zebrafish to Kalanchoe pinnata (Lam.) Pers leaf - KPL: Implications for medicinal use

Abstract

The prevalence of depression and anxiety is high during pregnancy. Several traditional medicines use the plant Kalanchoe pinnata (Lam.) Pers. (KP) to treat emotional disorders, inflammation, and to prevent preterm delivery, but the effects on the exposed offspring and the mechanism behind these events remain unknown. In this work, integrated systems toxicology (INSYSTA) was used to investigate traditional toxicological outcomes and behavioral performance in zebrafish larvae after chronic exposure (from 2 to 96 hpf) to K. pinnata leaf extracts (KPL). We investigated light/dark preference, thigmotaxis and locomotor activity parameters, followed by gene expression and systems biology approaches to discover the mechanisms behind toxicological endpoint and phenomics. The embryos exposed to 700 mg/L KPL showed retarded development including hatching delay. Larvae exposed to 500 mg/L KPL resulted in decreased dark avoidance and increased locomotor activity, while 700 mg/L showed opposite effects. The INSYSTA revealed sixteen genes down-regulated after KPL chronic treatment; they are involved in folding, sorting, and degradation of proteins as well as DNA replication and repair mechanisms. This may result in deregulation of the organismal functions, including those of immune and endocrine systems. These physiological changes appear to make embryos more sensitive to infections and disorders that resemble 47 human diseases. These findings suggest that the medicinal use of plant extracts requires strict toxicological, pharmacological, and medical supervision. At the same time, it suggests a polypharmacological pathway for KPL extract that goes beyond preventing premature delivery and controlling anxiety.