Folic acid mitigates the developmental and neurotoxic effects of bisphenol A in zebrafish by inhibiting the oxidative stress/JNK signaling pathway

Ruijing Li; Weili Yang; Xingxue Yan; Xinkui Zhou; Xiaorui Song; Cuihua Liu; Yaodong Zhang; Jitong Li

Ecotoxicology and Environmental Safety (Dec 2024)

Folic acid mitigates the developmental and neurotoxic effects of bisphenol A in zebrafish by inhibiting the oxidative stress/JNK signaling pathway

Ruijing Li,
Weili Yang,
Xingxue Yan,
Xinkui Zhou,
Xiaorui Song,
Cuihua Liu,
Yaodong Zhang,
Jitong Li

Affiliations

Ruijing Li: Children’s Hospital Affiliated to Zhengzhou University, Henan Engineering Research Center of Zebrafish Models for Human Disease and Drug Screening, Henan Neurodevelopment Engineering Research Center for Children, Zhengzhou 450018, China
Weili Yang: Children’s Hospital Affiliated to Zhengzhou University, Henan Engineering Research Center of Zebrafish Models for Human Disease and Drug Screening, Henan Neurodevelopment Engineering Research Center for Children, Zhengzhou 450018, China
Xingxue Yan: Children’s Hospital Affiliated to Zhengzhou University, Henan Engineering Research Center of Zebrafish Models for Human Disease and Drug Screening, Henan Neurodevelopment Engineering Research Center for Children, Zhengzhou 450018, China
Xinkui Zhou: Children’s Hospital Affiliated to Zhengzhou University, Henan Engineering Research Center of Zebrafish Models for Human Disease and Drug Screening, Henan Neurodevelopment Engineering Research Center for Children, Zhengzhou 450018, China
Xiaorui Song: Children’s Hospital Affiliated to Zhengzhou University, Henan Engineering Research Center of Zebrafish Models for Human Disease and Drug Screening, Henan Neurodevelopment Engineering Research Center for Children, Zhengzhou 450018, China
Cuihua Liu: Department of Nephrology and Rheumatology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou 450018, China
Yaodong Zhang: Children’s Hospital Affiliated to Zhengzhou University, Henan Engineering Research Center of Zebrafish Models for Human Disease and Drug Screening, Henan Neurodevelopment Engineering Research Center for Children, Zhengzhou 450018, China; Corresponding author.
Jitong Li: Children’s Hospital Affiliated to Zhengzhou University, Henan Engineering Research Center of Zebrafish Models for Human Disease and Drug Screening, Henan Neurodevelopment Engineering Research Center for Children, Zhengzhou 450018, China; Department of Nephrology and Rheumatology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou 450018, China; Corresponding author at: Children’s Hospital Affiliated to Zhengzhou University, Henan Engineering Research Center of Zebrafish Models for Human Disease and Drug Screening, Henan Neurodevelopment Engineering Research Center for Children, Zhengzhou 450018, China.

Journal volume & issue: Vol. 288
p. 117363

Abstract

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Bisphenol A (BPA) is a widespread environmental endocrine disruptor (EED) that can cause various environmental and health issues by inducing oxidative stress. The c-Jun N-terminal kinase (JNK) signaling pathway plays a crucial role in oxidative stress-mediated cellular damage. Although folic acid (FA) has demonstrated antioxidant properties, its potential protective effects against BPA-induced developmental and neurotoxicity, as well as the mechanisms involved in the JNK signaling pathway, are still not completely understood. Zebrafish embryos were exposed to different concentrations of BPA ranging from 20 to 40 µM, with or without treatment of 50 µM FA, starting at 6 hours post-fertilization (hpf). Various parameters such as hatchability, survival rate, body length, and heart rate were measured and analyzed. Transcriptome sequencing was conducted to study the changes in gene expression. Oxidative stress markers, including reactive oxygen species (ROS), lipid peroxidation (LPO), hydrogen peroxide (H2O2), and catalase (CAT) activity, were assessed. The expression of proteins related to the mitogen-activated protein kinase (MAPK)/JNK pathway was analyzed using western blot. Neurodevelopmental and apoptotic outcomes were evaluated through behavioral tests, immunofluorescence and RT-qPCR examinations. The study found that exposure to BPA led to a decrease in hatchability, survival, body length, heart rate, total antioxidant capacity and promoted apoptosis in zebrafish larvae. However, supplementation with FA was able to alleviate these negative effects. BPA exposure increased levels of ROS, LPO, and H2O2, while decreasing CAT activity in zebrafish larvae. Treatment with FA effectively reduced BPA-induced oxidative stress and restored antioxidant defense systems. Moreover, KEGG pathway enrichment analysis revealed that the MAPK signaling pathway was the most enriched signaling pathway. Further studies revealed that BPA activated the JNK signaling pathway, while FA suppressed this activation. Additionally, FA significantly improved BPA-induced neurobehavioral deficits and protected against neurocytological alterations. Our findings demonstrate that FA effectively protects against BPA-induced developmental and neurotoxic effects in zebrafish by suppressing oxidative stress and inhibiting the JNK signaling pathway. This study provides new strategies and insights for preventing BPA-induced developmental and neurotoxicity in aquatic organisms.

Published in Ecotoxicology and Environmental Safety

ISSN: 0147-6513 (Print); 1090-2414 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Technology: Environmental technology. Sanitary engineering: Environmental pollution; Geography. Anthropology. Recreation: Environmental sciences
Website: https://www.journals.elsevier.com/ecotoxicology-and-environmental-safety

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