Inflammation in the reproductive tract has become a serious threat to animal fertility. Recently, the role of peroxisome proliferator-activated receptor gamma (PPARγ) in the context of reproduction and the inflammatory response has been highlighted, but the role of PPARβ/δ has not been fully elucidated. The aim of the present study was to investigate the in vitro effect of PPARβ/δ ligands (agonist: L-165,041 and antagonist: GSK 3787) on the transcriptome profile of porcine endometrium during LPS-induced inflammation in the mid-luteal and follicular phases of the oestrous cycle (days 10-12 and 18-20, respectively) using the RNA-Seq method. During the mid-luteal phase of the oestrous cycle, the current study identified 145 and 143 differentially expressed genes (DEGs) after treatment with an agonist or antagonist, respectively. During the follicular phase of the oestrous cycle, 55 and 207 DEGs were detected after treatment with an agonist or antagonist, respectively. The detected DEGs are engaged in the regulation of various processes, such as the complement and coagulation cascade, NF-κB signalling pathway, or the pathway of 15-eicosatetraenoic acid derivatives synthesis. The results of the current study indicate that PPARβ/δ ligands are involved in the control of the endometrial inflammatory response.

01 Jul 2024·Environmental Health Perspectives

Investigation of Peroxisome Proliferator-Activated Receptor Genes as Requirements for Visual Startle Response Hyperactivity in Larval Zebrafish Exposed to Structurally Similar Per- and Polyfluoroalkyl Substances (PFAS)

Article

Author: Busch, Wibke ; Wood, Carmen ; Wehmas, Leah ; Gaballah, Shaza ; Omoyeni, Ifeoluwa ; Gutsfeld, Sebastian ; Bertotto, Luísa ; Howey, Xia Meng ; Herold, Nadia ; Wu, Gi-Mick ; Schweiger, Nicole ; Leuthold, David ; Schor, Jana ; Michaelis, Paul ; Klüver, Nils ; Vogs, Carolina ; Scholz, Stefan ; Tal, Tamara

BACKGROUNDPer- and polyfluoroalkyl Substances (PFAS) are synthetic chemicals widely detected in humans and the environment. Exposure to perfluorooctanesulfonic acid (PFOS) or perfluorohexanesulfonic acid (PFHxS) was previously shown to cause dark-phase hyperactivity in larval zebrafish.OBJECTIVESThe objective of this study was to elucidate the mechanism by which PFOS or PFHxS exposure caused hyperactivity in larval zebrafish.METHODSSwimming behavior was assessed in 5-d postfertilization (dpf) larvae following developmental (1-4 dpf) or acute (5 dpf) exposure to __-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__0.43-7.86μM PFOS, __-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__7.87-120μM PFHxS, or 0.4% dimethyl sulfoxide (DMSO). After developmental exposure and chemical washout at 4 dpf, behavior was also assessed at 5-8 dpf. RNA sequencing was used to identify differences in global gene expression to perform transcriptomic benchmark concentration-response (__-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__BMCT) modeling, and predict upstream regulators in PFOS- or PFHxS-exposed larvae. CRISPR/Cas9-based gene editing was used to knockdown peroxisome proliferator-activated receptors (ppars) pparaa/ab, pparda/db, or pparg at day 0. Knockdown crispants were exposed to __-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__7.86μM PFOS or 0.4% DMSO from 1-4 dpf and behavior was assessed at 5 dpf. Coexposure with the ppard antagonist GSK3787 and PFOS was also performed.RESULTSTransient dark-phase hyperactivity occurred following developmental or acute exposure to PFOS or PFHxS, relative to the DMSO control. In contrast, visual startle response (VSR) hyperactivity only occurred following developmental exposure and was irreversible up to 8 dpf. Similar global transcriptomic profiles, __-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__BMCT estimates, and enriched functions were observed in PFOS- and PFHxS-exposed larvae, and ppars were identified as putative upstream regulators. Knockdown of pparda/db, but not pparaa/ab or pparg, blunted PFOS-dependent VSR hyperactivity to control levels. This finding was confirmed via antagonism of ppard in PFOS-exposed larvae.DISCUSSIONThis work identifies a novel adverse outcome pathway for VSR hyperactivity in larval zebrafish. We demonstrate that developmental, but not acute, exposure to PFOS triggered persistent VSR hyperactivity that required ppard function. https://doi-org.libproxy1.nus.edu.sg/10.1289/EHP13667.

01 Feb 2024·Science of The Total Environment

PPARβ/δ-ANGPTL4 axis mediates the promotion of mono-2-ethylhexyl phthalic acid on MYCN-amplified neuroblastoma development

Article

Author: Liao, Yan-Ling ; Manzoor, Rakia ; Pei, De-Sheng ; Hamid, Naima ; Liu, Yiyun ; Wang, Jin-Xia ; Zhang, Bao-Fu

Di-2-ethylhexyl phthalic acid (DEHP) is one of the most widely used plasticizers in the industry, which can improve the flexibility and durability of plastics. It is prone to migrate from various daily plastic products through wear and leaching into the surrounding environment and decompose into the more toxic metabolite mono-2-ethylhexyl phthalic acid (MEHP) after entering the human body. However, the impacts and mechanisms of MEHP on neuroblastoma are unclear. We exposed MYCN-amplified neuroblastoma SK-N-BE(2)C cells to an environmentally related concentration of MEHP and found that MEHP increased the proliferation and migration ability of tumor cells. The peroxisome proliferator-activated receptor (PPAR) β/δ pathway was identified as a pivotal signaling pathway in neuroblastoma, mediating the effects of MEHP through transcriptional sequencing analysis. Because MEHP can bind to the PPARβ/δ protein and initiate the expression of the downstream gene angiopoietin-like 4 (ANGPTL4), the PPARβ/δ-specific agonist GW501516 and antagonist GSK3787, the recombinant human ANGPTL4 protein, and the knockdown of gene expression confirmed the regulation of the PPARβ/δ-ANGPTL4 axis on the malignant phenotype of neuroblastoma. Based on the critical role of PPARβ/δ and ANGPTL4 in the metabolic process, a non-targeted metabolomics analysis revealed that MEHP altered multiple metabolic pathways, particularly lipid metabolites involving fatty acyls, glycerophospholipids, and sterol lipids, which may also be potential factors promoting tumor progression. We have demonstrated for the first time that MEHP can target binding to PPARβ/δ and affect the progression of neuroblastoma by activating the PPARβ/δ-ANGPTL4 axis. This mechanism confirms the health risks of plasticizers as tumor promoters and provides new data support for targeted prevention and treatment of neuroblastoma.

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Indication	Highest Phase	Country/Location	Organization	Date
Arthritis	Preclinical	FR	Centre Hospitalier Universitaire de Montpellier	-
Neoplasms	Preclinical	US	The University of Texas MD Anderson Cancer Center	-

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