DEHP deregulates adipokine levels and impairs fatty acid storage in human SGBS-adipocytes

Abstract

DEHP is a plasticizer which has been used in plastic products of everyday use for decades. Studies in mice and murine cell culture models identified DEHP as an endocrine disruptor that may also act as an obesogen. As this is of high concern in respect of the worldwide obesity epidemic, our aim is the translation of these findings into a human model system. On the basis of DOHaD, we investigated the influence of an environmentally relevant dose of DEHP [50 µg/ml] on adipogenesis in the human cell culture model SGBS. Pre-adipocytes were exposed to DEHP and differentiated into mature adipocytes. At different stages of differentiation, markers of adipogenesis like GLUT4, FABP4, LPL and PPARs, and of signaling pathways like AMPK/ACC2, JAK/STAT and MAPK were analyzed. Functional markers like adipokine secretion and triglyceride content as well as ROS production were measured in mature adipocytes. We found significantly lower expression levels of adipogenic markers, a reduction in lipid accumulation, higher leptin- and reduced adiponectin levels in the supernatant of treated adipocytes. Moreover, ROS production was significantly elevated after DEHP-exposure. In conclusion, DEHP led to lower grade of adipogenic differentiation in human SGBS-adipocytes under the chosen conditions.

The endocrine disruptor DEHP and the ECS: analysis of a possible crosstalk

“…In proof of the efficacy of the present experiments, we investigated the DEHP action on adipokines. In agreement to our recent data (53), adiponectin was decreased and leptin was increased after DEHP exposure in mature SGBS adipocytes. Notably, in murine 3T3-derived adipocytes, DEHP reduced the cellular lipid content and adiponectin but increased the cell proliferation (14).…”

“…This is in agreement with results of previous studies in human adipocyte precursor cells, assuming differentiation to be correlated with the development of insulin sensitivity in mature adipocytes (59,60). As already described, DEHP exposure did not influence cell proliferation, but impaired adipogenic differentiation and lowered the lipid content of mature adipocytes (53). In proof of the efficacy of the present experiments, we investigated the DEHP action on adipokines.…”

“…The herein investigated receptors and enzymes of the ECS were not altered by DEHP. As shown before, DEHP did not affect the protein amount of PPARalpha and PPARgamma in SGBS (53). However, DEHP-mediated alterations on PPARs was reported in both directions as assessed in rodent in vitro and in vivo experiments (14,16,17,61), which points toward species-specific effects.…”

“…During the induction phase (day 0 to day 4), cells were exposed to a final DEHP concentration of 128 µM (50 µg/mL) and a concentration of 0.1% DMSO in the culture media, whereas controls were run as vehicle controls with 0.1% DMSO only. These experimental conditions are based on in-vitro investigations of our group previously performed in murine C3H10-T1/2 mesenchymal stem cells identifying the induction phase as a particularly vulnerable exposure window of adipogenesis (17,52) and in the SGBS cell model revealing effective but non-toxic concentrations of used substances (53). Furthermore, the herein applied DEHP concentration is considered as environmentally relevant (54,55,56).…”

The impact of di-2-ethylhexyl phthalate on sperm fertility

“…Interestingly, DEHP increases ROS generation in various cells and tissues, including hepatocytes, adipocytes, and testis (Y. Huang et al 2019;Kasahara et al 2002;Schaedlich et al 2018). However, DEHP's ability to alter sperm ROS production has not been studied.…”