Effects and underlying cellular pathway involved in the impairment of the neurovascular unit following exposure of adult male mice to low doses of di(2-ethylhexyl) phthalate alone or in an environmental phthalate mixture

Abstract

We have previously shown that adult male mice exposure to low doses of di (2-ethylhexyl)phthalate (DEHP) impacts the blood-brain barrier (BBB) integrity and surrounding parenchyma in the medial preoptic area (mPOA), a key hypothalamic area involved in the male sexual behavior. BBB leakage was associated with a decrease in the endothelial tight junction accessory protein, zona occludens-1, and caveolae protein Cav-1, added to an inflammatory profile including glial activation accompanied by enhanced expression of inducible nitric oxide synthase. As this failure of BBB functionality in the mPOA could participate, at least in part, in reported alteration of sexual behavior following DEHP exposure, we explored the cellular pathway connecting cerebral capillaries and neurons. Two-month-old C57BL/6J male mice 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. The presence of androgen receptor (AR) and estrogen receptor-α (ERα) were first evidenced in brain capillaries. Protein levels of AR but not of ERα were reduced in cerebral capillaries after phthalate exposure. The amounts of basement membrane and cell-matrix interaction components were decreased, while matrix metalloprotease MMP-2 and MMP-9 activities were increased. Fluorojade® labelling suggested that exposure to phthalates also lead to a neurodegenerative process in the mPOA. Altogether, the data suggest that environmental exposure to endocrine disruptors such as phthalates, could alter AR/Cav-1 interaction, impacting a Cav-1/nitric oxide/MMP pathway. This would lead to disruption of the glio-neurovascular coupling which is essential to neuronal functioning.