A Mixture of Chemicals Found in Human Amniotic Fluid Disrupts Brain Gene Expression and Behavior in Xenopus laevis

Thyroid hormones (TH) are essential for normal brain development, influencing neural cell differentiation, migration, and synaptogenesis. Multiple endocrine-disrupting chemicals (EDCs) are found in the environment, raising concern for their potential effects on TH signaling and the consequences on neurodevelopment and behavior. While most research on EDCs investigates the effects of individual chemicals, human health may be adversely affected by a mixture of chemicals. The potential consequences of EDC exposure on human health are far-reaching and include problems with immune function, reproductive health, and neurological development. We hypothesized that embryonic exposure to a mixture of chemicals (containing phenols, phthalates, pesticides, heavy metals, and perfluorinated, polychlorinated, and polybrominated compounds) identified as commonly found in the human amniotic fluid could lead to altered brain development. We assessed its effect on TH signaling and neurodevelopment in an amphibian model (Xenopus laevis) highly sensitive to thyroid disruption. Fertilized eggs were exposed for eight days to either TH (thyroxine, T-4 10 nM) or the amniotic mixture (at the actual concentration) until reaching stage NF47, where we analyzed gene expression in the brains of exposed tadpoles using both RT-qPCR and RNA sequencing. The results indicate that whilst some overlap on TH-dependent genes exists, T-4 and the mixture have different gene signatures. Immunohistochemistry showed increased proliferation in the brains of T-4-treated animals, whereas no difference was observed for the amniotic mixture. Further, we demonstrated diminished tadpoles' motility in response to T-4 and mixture exposure. As the individual chemicals composing the mixture are considered safe, these results highlight the importance of examining the effects of mixtures to improve risk assessment.

Automated summary

Thyroid hormones (TH) are crucial for brain development, but endocrine-disrupting chemicals (EDCs) in the environment can potentially interfere with TH signaling and impact neurodevelopment and behavior. This study investigated the effects of an amniotic mixture containing commonly found EDCs on brain development and TH signaling using Xenopus laevis tadpoles. The results showed that while there were similarities in TH-dependent genes between thyroxine (T-4) and the amniotic mixture, they also had distinct gene signatures. T-4-treated tadpoles showed increased brain cell proliferation, whereas the amniotic mixture had no effect. Additionally, both T-4 and mixture exposure resulted in decreased tadpole motility. These findings highlight the importance of examining the effects of chemical mixtures for better risk assessment.