Disruption of thyroid hormone-dependent hypothalamic set-points by environmental contaminants

The hypothalamus integrates metabolic and endocrine signals. As such it represents a potential target for a wide spectrum of endocrine disrupting chemicals (EDCs). We investigated hypothalamic effects of two environmentally abundant xenobiotics, the flame-retardant tetrabromo bisphenol A (TBBPA) and the anti-fouling agent tributyltin (TBT). These EDCs affect endocrine signalling through different nuclear receptors including the thyroid hormone receptor (TR) or its partner, the retinoid X receptor (RXR). Promoter sequences of two hypothalamic genes implicated in metabolic control and regulated by thyroid hormone, thyrotropin-releasing hormone (Trh) and type 4 melanocortin receptor (Mc4r), were studied in vivo using reporter assays. Chronic exposure of gestating dams or acute exposure of their newborns to TBBPA abrogated activation of both Trh and Mc4r transcription. Exposure of lactating dams to TBT amplified activation of Trh without affecting Mc4r transcription. Thus, perinatal exposure to EDCs affecting nuclear receptor signalling modulates hypothalamic set-points controlling metabolic responses.