MEST mediates the impact of prenatal bisphenol A exposure on long-term body weight development

Abstract

BackgroundExposure to endocrine-disrupting chemicals can alter normal physiology and increase susceptibility to non-communicable diseases like obesity. Especially the prenatal and early postnatal period is highly vulnerable to adverse effects by environmental exposure, promoting developmental reprogramming by epigenetic alterations. To obtain a deeper insight into the role of prenatal bisphenol A (BPA) exposure in children’s overweight development, we combine epidemiological data with experimental models and BPA-dependent DNA methylation changes.MethodsBPA concentrations were measured in maternal urine samples of the LINA mother-child-study obtained during pregnancy (n = 552), and BPA-associated changes in cord blood DNA methylation were analyzed by Illumina Infinium HumanMethylation450 BeadChip arrays (n = 472). Methylation changes were verified by targeted MassARRAY analyses, assessed for their functional translation by qPCR and correlated with children’s body mass index (BMI) z scores at the age of 1 and 6 years. Further, female BALB/c mice were exposed to BPA from 1 week before mating until delivery, and weight development of their pups was monitored (n ≥ 8/group). Additionally, human adipose-derived mesenchymal stem cells were treated with BPA during the adipocyte differentiation period and assessed for exposure-related epigenetic, transcriptional and morphological changes (n = 4).ResultsIn prenatally BPA-exposed children two CpG sites with deviating cord blood DNA-methylation profiles were identified, among them a hypo-methylated CpG in the promoter of the obesity-associated mesoderm-specific transcript (MEST). A mediator analysis suggested that prenatal BPA exposure was connected to cord blood MEST promoter methylation and MEST expression as well as BMI z scores in early infancy. This effect could be confirmed in mice in which prenatal BPA exposure altered Mest promoter methylation and transcription with a concomitant increase in the body weight of the juvenile offspring. An experimental model of in vitro differentiated human mesenchymal stem cells also revealed an epigenetically induced MEST expression and enhanced adipogenesis following BPA exposure.ConclusionsOur study provides evidence that MEST mediates the impact of prenatal BPA exposure on long-term body weight development in offspring by triggering adipocyte differentiation.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0478-z) contains supplementary material, which is available to authorized users.

Maternal paraben exposure triggers childhood overweight development

“…Parabens have been shown to promote adipocyte differentiation in mouse fibroblasts 23 . To evaluate a potential direct effect of parabens on human adipocyte differentiation an established human mesenchymal stem cell differentiation assay was applied 9 . Adipocyte differentiation, assessed by the cell index values of impedance-based real-time monitoring and by the amount of triglyceride storage, was not affected by nBuP exposure (Fig.…”

“…Human adipose-derived mesenchymal stem cells (MSC) derived by a female donor (ATCC, LGC Standards (Wesel, Germany), PCS-500-011; LOT #59753760) and appropriate culture media were purchased from ATCC (LGC Standards,Wesel, Germany, PCS-500-030, PCS-500-040 and PCS-500-050). Cells were cultured under normal conditions at 37°C, 5% CO 2 and 95% humidity according to the manufacturer's instructions 9 . In brief, for adipocyte differentiation MSCs passage 3-5 were seeded at 9.000 cells per cm 2 in a 96-well plate and grown to 70% confluence.…”

“…In critical time windows such as the foetal development perturbations of the physiological endocrine and metabolic signalling can result in long lasting health effects [6][7][8] . Synthetic chemicals interfering with the endocrine system (endocrine disrupting chemicals, EDC) represent a classical example for environmental factors contributing to programming towards overweight and obesity, in particular in the perinatal period 9 . EDCs are added to products as preservatives or plasticizers, for antimicrobial and antifungal function or as flame retardants 10,11 .…”

Potential Mechanisms of Bisphenol A (BPA) Contributing to Human Disease

“…Interestingly, miR-21-a-5p overexpression mitigates BPA obesogenic effect in vivo [147]. In humans, prenatal BPA exposure seems to favor overweight phenotype in children, modifying methylation of CpG sites, including one hypo-methylated CpG in the promoter of the mesoderm-specific transcript gene (MEST) encoding an obesity-related member of the α/β hydrolase fold family [148].…”

Beyond the looking glass: recent advances in understanding the impact of environmental exposures on neuropsychiatric disease

“…Exposure to bisphenol-A (BPA) in these mice leads to shifts in DNA methylation levels at the Agouti coat color locus and ultimately, an altered coat color [89]. BPA has also been associated with global and site-specific changes in DNA methylation and histone tail modifications in human observational studies [90][91][92]. A cross-organism study found mouse liver DNA methylation levels at the STAT3 locus were altered in response to perinatal exposure to BPA and were also relevant to adult health outcomes [93].…”