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

doi:10.1016/j.ecoenv.2024.117363

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

Ecotoxicol Environ Saf. 2024 Nov 19:288:117363. doi: 10.1016/j.ecoenv.2024.117363. Online ahead of print.

Authors

Ruijing Li¹, Weili Yang¹, Xingxue Yan¹, Xinkui Zhou¹, Xiaorui Song¹, Cuihua Liu², Yaodong Zhang³, Jitong Li⁴

Affiliations

¹ 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.
² Department of Nephrology and Rheumatology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou 450018, China.
³ 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. Electronic address: syek@163.com.
⁴ 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. Electronic address: ljtsuc@yeah.net.

PMID: 39566264
DOI: 10.1016/j.ecoenv.2024.117363

Abstract

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.

Keywords: Bisphenol A; Developmental and neurotoxicity; Folic acid; JNK/MAPK; Oxidative stress; Zebrafish.