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.

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.

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.

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.

Involvement of Testosterone Signaling in the Integrity of the Neurovascular Unit in the Male: Review of Evidence, Contradictions, and Hypothesis.

Age-related central nervous system function decline and increased susceptibility of females compared to males with respect to prevalence of several neurodegenerative and neuropsychiatric diseases are both based on the principle that hormonal factors could be involved. These cerebral disorders are characterized by an alteration of blood-brain barrier (BBB) properties and chronic neuroinflammation, which lead to disease progression. Neuroinflammation, in turn, contributes to BBB dysfunction. The BBB and its environment, called the neurovascular unit (NVU), are crucial for cerebral homeostasis and neuronal function. Interestingly, sex steroids influence BBB properties and modulate neuroinflammatory responses. To date however, the majority of work reported has focused on the effects of estrogens on BBB function and neuroinflammation in female mammals. In contrast, the effects of testosterone signaling on the NVU in males are still poorly studied. The aim of this review was to summarize and discuss the literature, providing insights and contradictions to highlight hypothesis and the need for further investigations.