Disruption of the blood-brain barrier and its close environment following adult exposure to low doses of di(2-ethylhexyl)phthalate alone or in an environmental phthalate mixture in male mice

Abstract

We have previously shown that adult male mice exposure to low doses of di(2-ethylhexyl)phthalate (DEHP) alters neural function and behaviour. Whether such exposure also affects the integrity and function of the blood-brain barrier (BBB) remained to be explored. The impact of adult exposure to low doses of DEHP alone or in an environmental phthalate mixture on the BBB integrity and surrounding parenchyma was studied in male mice. Two-month-old C57BL/6J males were orally exposed for 6 weeks to DEHP alone (5, and 50 μg/kg/day) or to DEHP (5 μg/kg/day) in an environmental phthalate mixture. BBB permeability, glial activation and neuroinflammation were investigated in the hypothalamic medial preoptic area (mPOA) and hippocampus involved, respectively on the reproductive and cognitive functions. Exposure to DEHP alone or in a phthalate mixture increased BBB permeability and affected the endothelial accessory tight junction protein zona occludens-1 and caveolae protein Cav-1 in the mPOA and the hippocampal CA1 and CA3 areas. This was associated with an inflammatory profile including astrocyte activation accompanied by enhanced expression of inducible nitric oxide synthase in the mPOA, and a microglial activation in the mPOA and the hippocampal CA1 and CA3 areas. The protein levels of the inflammatory molecule cyclooxygenase-2 were increased in activated microglial cells of the exposed mPOA. None of the major effects induced by DEHP alone or in a mixture was detected in the hippocampal dendate gyrus. The data highlight that environmental exposure to endocrine disruptors such as phthalates, could represent a risk factor for the cerebrovascular function.