metabolic disorders and potential biomarkers associated with the developmental toxicity

Medicilon’s toxicology department has professional teams with rich experience in toxicology studies. We offer high-quality data and rapid turnaround period to support drug discovery and development. Our toxicological studies are conducted in various animal species. The toxicological evaluation from dose design, in-life studies to histology and pathology testing along with toxicokinetics studies are all compliant with GLP or NON-GLP standards. Our study platform is certified as one of the Shanghai Public Service Research Platforms.

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Tetrabromobisphenol A and tetrachlorobisphenol A are halogenated bisphenol A (H-BPA), and has raised concerns about their adverse effects on the development of fetuses and infants, however, the molecular mechanisms are unclear, and related metabolomics studies are limited. Accordingly, a metabolomics study based on gas chromatography-mass spectrometry was employed to elucidate the molecular developmental toxicology study of H-BPA using the marine medaka (Oryzias melastigmas) embryo model. Here, we revealed decreased synthesis of nucleosides, amino acids and lipids, and disruptions in the TCA (tricarboxylic acid) cycle, glycolysis and lipid metabolism, thus inhibiting the developmental processes of embryos exposed to H-BPA. Unexpectedly, we observed enhanced neural activity accompanied by lactate accumulation and accelerated heart rates due to an increase in dopamine pathway and a decrease in inhibitory neurotransmitters following H-BPA exposure. Notably, disorders of the neural system, and disruptions in glycolysis, the TCA cycle, nucleoside metabolism, lipid metabolism, glutamate and aspartate metabolism induced by H-BPA exposure were heritable. Furthermore, lactate and dopa were identified as potential biomarkers of the developmental toxicity of H-BPA and related genetic effects. This study has demonstrated that the metabolomics approach is a useful tool for obtaining comprehensive and novel insights into the molecular developmental toxicity of environmental pollutants.

Tetrabromobisphenol A (TBBPA) and tetrachlorobisphenol A (TCBPA) are halogenated derivatives of bisphenol A (H-BPA); and are used as flame retardants worldwide. Owing to their high levels of production, widespread usage, low volatility, high lipophilicity and recalcitrance, TBBPA and TCBPA persist in the environment and have been detected in wildlife, human serum, umbilical blood and breast milk.

Major sources of human exposure to TBBPA and TCBPA mainly include dust ingestion, diet, dermal contact and air inhalation. TBBPA exposure levels in infants were found to be and 13 times higher than those in toddlers, children, teenagers and adults, respectively. Additionally, the average level of TBBPA intake via human milk in nursing infants aged 1–6 months was 19.9 times higher than that in adults. Moreover, the average mother-to-infant TBBPA transfer ratio was 3.04, and TBBPA levels were 2–5 times higher in infants aged 1–3 months than in mothers, and decreased significantly with age. Notably, fetuses and infants were more vulnerable to environmental toxins than the other age groups. Accordingly, the potential toxic effects of TBBPA and TCBPA on the development of fetuses and infants are worthy of comprehensive investigations.

Accumulating data have demonstrated the toxic effects of H-BPA on biological development, in addition to the reproductive, nervous and endocrine system. As illustrated in zebrafish, TBBPA exposure cause trunk edema, tail malformations, delayed hatching time, decreased hatching rates, and increased mortality of embryos and larvae. A one-generation reproduction study of Wistar rats revealed delayed sexual development in females due to TBBPA exposure Moreover, increased DNA damage and apoptosis of testicular cells have been reported in mice exposed to TBBPA. However, the molecular mechanisms underlying the developmental toxicity of H-BPA are unclear. To the best of our knowledge, metabolomics studies examining the developmental toxicity of H-BPA have not been conducted.

The marine medaka (Oryzias melastigma) model has many advantages, such as a short generation time, transparent eggs that facilitate experimental observations and manipulations, high levels of egg production, eggs and larvae that are sensitive to environmental pollutants, and the fact that it has been widely applied in toxicology studies. Accordingly, O. melastigma embryos were used as a model to elucidate the potential effects of H-BPA on developmental toxicity in a comprehensive manner by employing metabolomics based on gas chromatography-mass spectrometry (GC-MS), which has been shown to be a useful approach for discovering metabolic disorders related to environmental toxicology. First, embryos were exposed to TBBPA and TCBPA to evaluate the developmental toxicity of H-BPA. Subsequently, F1 embryos were collected for a metabolomics analysis to determine the developmental toxicology of H-BPA and related genetic effects after F0 and F1 exposure to H-BPA. The aim of the present study was to provide the first comprehensive and novel understanding of metabolic disorders and potential biomarkers associated with the developmental toxicity of H-BPA and related genetic effects.