Thyroid Disrupting Chemicals in Mixture Perturb Thymocyte Differentiation in Xenopus laevis Tadpoles

Abstract

Abstract Endocrine disrupting chemicals (EDCs) can perturb the hypothalamic-pituitary-thyroid axis affecting human and wildlife health. Thyroid hormones (TH) are crucial regulators of metabolism, growth, and differentiation. The perinatal stage is most reliant on TH, thus vulnerable to TH disrupting chemicals. Dysregulation of TH signaling during perinatal development can weaken T cell function in maturity, raising the question of whether TH disrupting chemicals can perturb thymocyte development. Using Xenopus laevis tadpoles as model, we determined TH disrupting effects and thymocyte alterations following exposure to a mixture of common waterborne TH disrupting chemicals at concentrations similar to those found in contaminated water. This mixture included naphthalene, ethylene glycol, ethoxylated nonylphenol, and octylphenol, which have documented TH disrupting activity. Besides hypertrophy-like pathology in the thyroid gland and delayed metamorphosis, exposure to the mixture antagonized TH receptor-induced transcription of the Krüppel-like factor 9 transcription factor and significantly raised thyroid-stimulating hormone gene expression in the brain, two genes that modulate thymocyte differentiation. Importantly, exposure to this mixture reduced the number of Xenopus immature cortical thymocyte-specific-antigen (CTX+) and mature CD8+ thymocytes, whereas co-exposure with exogenous TH (T3) abolished the effect. When each chemical of the mixture was individually tested, only ethylene glycol induced significant antagonist effects on brain, thymic gene expression, and CD8+ thymocytes. These results suggest that EDCs in mixture are more potent than each chemical alone to perturb thymocyte development through TH-dependent pathway, and provide a starting point to research TH influence on thymocyte development.