Effects of Dicyclohexyl Phthalate Exposure on PXR Activation and Lipid Homeostasis in Mice.

BACKGROUND: Exposure to plastic-associated endocrine disrupting chemicals (EDCs) has been associated with an increased risk of cardiovascular disease (CVD) in humans. However, the underlying mechanisms for this association are unclear. Many EDCs have been shown to function as ligands of the nuclear receptor pregnane X receptor (PXR), which functions as xenobiotic sensor but also has pro-atherogenic effects in vivo. OBJECTIVE: We sought to investigate the contribution of PXR to the adverse effects dicyclohexyl phthalate (DCHP), a widely used phthalate plasticizer, on lipid homeostasis and CVD risk factors. METHODS: Cell-based assays, primary organoid cultures, and PXR conditional knockout and PXR-humanized mouse models were used to investigate the impact of DCHP exposure on PXR activation and lipid homeostasis in vitro and in vivo. Targeted lipidomics were performed to measure circulating ceramides, novel predictors for CVD. RESULTS: DCHP was identified as a potent PXR-selective agonist that led to higher plasma cholesterol levels in wild-type mice. DCHP was then demonstrated to activate intestinal PXR to elicit hyperlipidemia by using tissue-specific PXR-deficient mice. Interestingly, DCHP exposure also led to higher circulating ceramides in a PXR-dependent manner. DCHP-mediated PXR activation stimulated the expression of intestinal genes mediating lipogenesis and ceramide synthesis. Given that PXR exhibits considerable species-specific differences in receptor pharmacology, PXR-humanized mice were also used to replicate these findings. DISCUSSION: Although the adverse health effects of several well-known phthalates have attracted considerable attention, little is known about the potential impact of DCHP on human health. Our studies demonstrate that DCHP activated PXR to induce hypercholesterolemia and ceramide production in mice. These results indicate a potentially important role of PXR in contributing to the deleterious effects of plastic-associated EDCs on cardiovascular health in humans. Testing PXR activation should be considered for risk assessment of phthalates and other EDCs. https://doi.org/10.1289/EHP9262.

Is it safe to leave an ECMO circuit primed?

Extracorporeal membrane oxygenation (ECMO) is a means of life support for failing patients who require extreme life-saving measures due to failure of their heart, lungs or both organs. In a patient suffering cardiac arrest, the faster circulation via cardiopulmonary resuscitation (CPR) can be instituted the better the outcome is. If an ECMO circuit needs to be built and primed it may add significant minutes to the response time. The purpose of this study is to test for any growth in primed ECMO circuits at given time intervals to prove the safety of leaving an ECMO circuit primed. This, in turn, may lead to decreased response time, with an arrest and the placement of the arresting patient on ECMO. Five ECMO circuits were set up, primed and sampled for bacterial growth at 0, 24, 48 and 72 hours and then at one-week intervals, with an end point of four weeks. No bacterial growth was found at any point during the sampling process.