Embryonic exposure to Mono(2-ethylhexyl) phthalate (MEHP) disrupts pancreatic organogenesis in zebrafish (Danio rerio)

Abstract

Mono(2-ethylhexyl) phthalate (MEHP) is the bioactive metabolite of di(2-ethylhexyl) phthalate, a plasticizing agent and persistent environmental contaminant associated with obesity, developmental abnormalities, and oxidative stress. Nrf2 (Nfe2l2) is a transcription factor that regulates cytoprotective genes as part of the adaptive antioxidant response. We previously identified the pancreas as a sensitive target of oxidative stress during embryonic development. The goals of this study were to 1) characterize the effects of MEHP exposure on pancreatic development, and 2) determine whether oxidative stress contributes to MEHP embryotoxicity. Zebrafish (Danio rerio) embryos from AB wildtype and Tg(ins:GFP;nrf2a) were exposed to 0 or 200 μg/L MEHP at 3 h post fertilization (hpf) through 168 hpf to assess pancreatic organogenesis. MEHP exposure significantly decreased β-cell area at all timepoints (48, 72, 96, 168 hpf), but Nrf2a did not significantly protect against islet hypomorphism. Tg(gcga:GFP) embryos exposed to MEHP showed a decrease in α-cell area in the islet across the same timepoints. Tg(ptf1a:GFP) embryos were assessed at 80 and 168 hpf for exocrine pancreas length. MEHP exposure decreased growth of the exocrine pancreas. Expression of pancreas genes insa, sst2 and ptf1a was significantly reduced by MEHP exposure compared to controls. Glutathione (GSH) concentrations and redox potentials were quantified at 72 hpf by HPLC, but no significant changes were observed. However, expression of the GSH-related genes gstp1 and gsr were significantly altered by MEHP exposure. These data indicate that the developing pancreas is a sensitive target tissue of embryonic exposure to MEHP.

Pancreatic beta cells are a sensitive target of embryonic exposure to butylparaben in zebrafish (Danio rerio)

“…These effects occur alongside disruptions in the glutathione and cysteine redox systems in the embryo, but the relationship between redox stress and occurrence of these deformities requires further investigation. This study, along with others (e.g., Jacobs et al, ; Sant et al, ; Timme‐Laragy et al, ), also highlights the utility of the Tg(ins:GFP) zebrafish embryo to screen for toxicants that pose potential hazards to the developing pancreas.…”

“…This may also indicate different mechanisms occurring at different ends of the doseresponse range. For instance, the islet measurements of control embryos show consolidation of this structure as the larvae mature (this paper and [Jacobs et al, 2018]), and it may be that low concentrations of butylparaben interfere with this F IGUR E 5 Gene Expression of pancreas and glutathione genes. Wildtype AB embryos were exposed daily to DMSO, 250, 500, or 3,000 nM butylparaben, and were collected at 78 hpf.…”

Developmental Exposure to Endocrine Disrupting Chemicals and Type 1 Diabetes Mellitus

“…In addition to these rodent studies, experimental studies on zebrafish embryos, another animal model used to evaluate the effects of EDCs, also show that developmental exposure to numerous chemicals affect the development of the pancreas and beta cells in utero . Developmental exposure to a number of chemicals, including arsenic, phthalates, the POPs polychlorinated biphenyls (PCBs), and perfluorooctanesulfonic acid (PFOS) (a PFC), affected the pancreatic development of zebrafish embryos, resulting in flawed development of the islets and beta cells ( 43 – 46 ). For example, exposure to a dioxin-like PCB resulted in inappropriate development of the pancreatic islets and beta cells in zebrafish embryos ( 46 ).…”

“…Exposure to PFOS led to decreased pancreatic islet size and changes in islet morphology in embryos ( 45 ). Mono(2-ethylhexyl) phthalate (MEHP), a metabolite of DEHP, affected pancreatic development, reducing beta cell area, and affected gene expression in embryos as well ( 43 ). In sum, these experimental studies illustrate that developmental exposure to numerous EDCs can affect the development of the pancreas and specifically the beta cells in utero .…”

DEHP chronic exposure disturbs the gut microbial community and metabolic homeostasis: Gender-based differences in zebrafish

“…The elevated levels of DEHP have been reported in freshwater resources, which provides water supply for drinking and domestic utilities, and this could ultimately pose a threat to environmental and human health [38]. In the previous studies, the toxicity of DEHP and its derivative MEHP had mainly focused on the developmental and reproduction effects or organogenesis through various biological pathways in fish [39][40][41]. However, the eco-toxicological risks of DEHP with environmental concentrations on freshwater fish health including the development and intestinal homeostasis, especially their underlying relationships with the disruption of intestinal bacterial functions were still unclear.…”