In vitro to in vivo evidence for chemical disruption of glucocorticoid receptor signaling

Abstract

Glucocorticoids are steroid hormones that regulate stress homeostasis, metabolism, and inflammatory responses. Dysregulation of the glucocorticoid receptor (GR) is linked to diseases such as obesity, mood disorders, and immune dysfunction. Endocrine-disrupting chemicals (EDCs) are widespread environmental contaminants known to interfere with hormone signaling, but their impact on glucocorticoid signaling remains unclear. While several GR-disrupting compounds have been identified in vitro, their in vivo effects remain largely unknown. In this study, we identified the agricultural agents dichlorodiphenyltrichloroethane (DDT) and ziram as GR-disruptors in vitro. In vivo, corticosterone co-treatment with DDT or the GR antagonist RU-486 inhibited the expression of classic GR-regulated transcripts in the liver. Furthermore, chronic exposure to DDT or RU-486 significantly reduced circulating B and T lymphocyte populations, respectively. These findings underscore the need to translate in vitro discoveries into in vivo models to assess the clinical relevance of GR-disrupting compounds. Moreover, they highlight the potential for xenobiotic-induced GR disruption to impair metabolic and immune homeostasis, potentially increasing disease susceptibility.