Effects of Gestational Arsenic Exposures on Placental and Fetal Development in Mice: The Role of Cyr61 m 6 A .

Autor: Song YP; Department of Toxicology, Anhui Medical University, Hefei, Anhui, China., Lv JW; Department of Toxicology, Anhui Medical University, Hefei, Anhui, China., Zhang ZC; Department of Toxicology, Anhui Medical University, Hefei, Anhui, China., Qian QH; Department of Toxicology, Anhui Medical University, Hefei, Anhui, China., Fan YJ; Department of Toxicology, Anhui Medical University, Hefei, Anhui, China.; Second Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China., Chen DZ; Wuxi Maternity and Child Health Care Hospital, Wuxi, Jiangsu, China., Zhang H; Wuxi Maternity and Child Health Care Hospital, Wuxi, Jiangsu, China., Xu FX; Department of Toxicology, Anhui Medical University, Hefei, Anhui, China., Zhang C; Department of Toxicology, Anhui Medical University, Hefei, Anhui, China., Huang Y; Department of Toxicology, Anhui Medical University, Hefei, Anhui, China., Wang H; Department of Toxicology, Anhui Medical University, Hefei, Anhui, China., Wei W; Key Laboratory of Anti-Inflammatory and Immune Medicine, Education Ministry of China, Anhui Medical University, Hefei, Anhui, China., Xu DX; Department of Toxicology, Anhui Medical University, Hefei, Anhui, China.
Jazyk: angličtina
Zdroj: Environmental health perspectives [Environ Health Perspect] 2023 Sep; Vol. 131 (9), pp. 97004. Date of Electronic Publication: 2023 Sep 08.
DOI: 10.1289/EHP12207
Abstrakt: Background: Several epidemiological investigations demonstrated that maternal arsenic (As) exposure elevated risk of fetal growth restriction (FGR), but the mechanism remains unclear.
Objectives: This study aimed to investigate the effects of gestational As exposure on placental and fetal development and its underlying mechanism.
Methods: Dams were exposed to 0.15, 1.5, and 15 mg / L NaAsO 2 throughout pregnancy via drinking water. Sizes of fetuses and placentas, placental histopathology, and glycogen content were measured. Placental RNA sequencing was conducted. Human trophoblasts were exposed to NaAsO 2 ( 2 μ M ) to establish an in vitro model of As exposure. The mRNA stability and protein level of genes identified through RNA sequencing were measured. N 6 -Methyladenosine ( m 6 A ) modification was detected by methylated RNA immunoprecipitation-quantitative real-time polymerase chain reason (qPCR). The binding ability of insulin-like growth factor 2 binding protein 2 to the gene of interest was detected by RNA-binding protein immunoprecipitation-qPCR. Intracellular S-adenosylmethionine (SAM) and methyltransferase activity were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and colorimetry, respectively. In vitro As + 3 methyltransferase (As3MT) knockdown or SAM supplementation and in vivo folic acid (FA) supplementation were used to evaluate the protective effect. A case-control study verified the findings.
Results: Sizes of fetuses (exposed to 1.5 and 15 mg / L NaAsO 2 ) and placentas (exposed to 15 mg / L NaAsO 2 ) were lower in As-exposed mice. More glycogen + trophoblasts accumulated and the expression of markers of interstitial invasion was lower in the 15 mg / L NaAsO 2 -exposed mouse group in comparison with control. Placental RNA sequencing identified cysteine-rich angiogenic inducer 61 ( Cyr61 ) as a candidate gene of interest. Mechanistically, mice and cells exposed to As had lower protein expression of CYR61, and this was attributed to a lower incidence of Cyr61 m 6 A . Furthermore, cells exposed to As had lower methyltransferase activity, suggesting that this could be the mechanism by which Cyr61 m 6 A was affected. Depletion of intracellular SAM, a cofactor for m 6 A methyltransferase catalytic domain, partially contributed to As-induced methyltransferase activity reduction. Either As3MT knockdown or SAM supplementation attenuated As-induced Cyr61 m 6 A down-regulation. In mice, FA supplementation rescued As-induced defective trophoblastic invasion and FGR. In humans, a negative correlation between maternal urinary As and plasma CYR61 was observed in infants who were small for gestational age.
Discussion: Using in vitro and in vivo models, we found that intracellular SAM depletion-mediated Cyr61 m 6 A down-regulation partially contributed to As-induced defective trophoblastic invasion and FGR. https://doi.org/10.1289/EHP12207.
Databáze: MEDLINE
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