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YTHDF2-mediated regulations bifurcate BHPF-induced programmed cell deaths

National Science Review 2023 31 citations ? Citation count from OpenAlex, updated daily. May differ slightly from the publisher's own count.
Jiebo Lin, Guankai Zhan, Jinfeng Liu, Yasen Maimaitiyiming, Zhiping Deng, Baohua Li, Kunhui Su, Jiafeng Chen, Siqi Sun, Wanlin Zheng, Xianghui Yu, Feng He, Xiaodong Cheng, Lingfang Wang, Bin Shen, Ziqin Yao, Xinquan Yang, Jian Zhang, Wentao He, Hengyu Wu, Hua Naranmandura, Kao-Jung Chang, Junxia Min, Jun Ma, Mikael Björklund, Pengfei Xu, Fudi Wang, Chih-Hung Hsu

Summary

Researchers found that BHPF, a chemical substitute for BPA commonly used in plastic manufacturing, was detected in 14% of pregnant women's blood samples and caused heart and blood vessel defects in zebrafish embryos. The chemical works by disrupting a key RNA-regulating protein, triggering different types of cell death in different tissues. This study raises concerns that BPA replacement chemicals in plastics may not be safer and could pose risks to developing babies.

Body Systems
Cardiovascular Immune
Models
Zebrafish

N6-methyladenosine (m6A) is a critical regulator in the fate of RNA, but whether and how m6A executes its functions in different tissues remains largely obscure. Here we report downregulation of a crucial m6A reader, YTHDF2, leading to tissue-specific programmed cell deaths (PCDs) upon fluorene-9-bisphenol (BHPF) exposure. Currently, Bisphenol A (BPA) substitutes are widely used in plastic manufacturing. Interrogating eight common BPA substitutes, we detected BHPF in 14% serum samples of pregnant participants. In a zebrafish model, BHPF caused tissue-specific PCDs triggering cardiac and vascular defects. Mechanistically, BHPF-mediated downregulation of YTHDF2 reduced YTHDF2-facilitated translation of m6A-gch1 for cardiomyocyte ferroptosis, and decreased YTHDF2-mediated m6A-sting1 decay for caudal vein plexus (CVP) apoptosis. The two distinct YTHDF2-mediated m6A regulations and context-dependent co-expression patterns of gch1/ythdf2 and tnfrsf1a/ythdf2 contributed to YTHDF2-mediated tissue-specific PCDs, uncovering a new layer of PCD regulation. Since BHPF/YTHDF2-medaited PCD defects were also observed in mammals, BHPF exposure represents a potential health threat.

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