Reproductive toxicology (Elmsford, N.Y.) · 2026
Association of Phthalates with miR-3651, ATP6AP2, and SEC63 Dysregulation in Missed Abortion: Clinical and In Vitro Evidence.
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Ou Liujuan, Li Wanhui, Zhao Ranran, Wen Junshang, Liao Tierong, Huang Huishen, Liang Jun, He Yuxian, Huang Shimeng, Qiu Xiaoqiang, Wang Caizhu, Huang Dongping
Аннотация
BACKGROUND: Missed abortion (MA) is a major pregnancy complication. Although phthalates (PAEs) are recognized reproductive toxicants and miR-3651 has been linked to embryogenesis, the interplay between them in the pathogenesis of MA remains unknown.
METHODS: The villous tissues were collected from 50 MA patients and 50 women undergoing elective termination. PAE exposure levels and the expression of miR-3651, ATP6AP2 and SEC63 were quantified. An in vitro PAEs exposure model was established in HTR-8/SVneo cells, and the expression of miR-3651, its target genes and related cytokines was measured.
RESULTS: In the MA group, miR-3651 was upregulated while ATP6AP2 and SEC63 were downregulated, accompanied by higher butyl benzyl phthalate (BBP) exposure (all p<0.05). LgBBP was significantly associated with MA (OR=4.434; 95% CI: 1.772, 11.094; p=0.001; q=0.019), whereas ATP6AP2 showed only a borderline inverse association (OR=0.354; p=0.051). LgMEHP (mono(2-ethylhexyl) phthalate) showed a nominal positive association with miR-3651 (β=0.610; 95% CI: 0.090, 1.129; p=0.022; q=0.110). Exploratory quantile g-computation (qgcomp) weights showed LgMEHP (43.36% of positive weights) and LgBBP (31.74% of negative weights) as the largest weight components for miR-3651 and ATP6AP2, respectively. In vitro, BBP and MEHP increased miR-3651 but decreased ATP6AP2 and SEC63 (p<0.05). Overexpression of miR-3651 downregulated PLGF and VEGF-A while upregulating IL-6, IL-17 and IFN-γ. Additionally, both BBP and MEHP reduced VEGF-A levels, while MEHP increased IL-6 levels (p < 0.05).
CONCLUSION: This study shows that phthalate exposure is associated with miR-3651 upregulation and downregulation of ATP6AP2 and SEC63 in MA.
METHODS: The villous tissues were collected from 50 MA patients and 50 women undergoing elective termination. PAE exposure levels and the expression of miR-3651, ATP6AP2 and SEC63 were quantified. An in vitro PAEs exposure model was established in HTR-8/SVneo cells, and the expression of miR-3651, its target genes and related cytokines was measured.
RESULTS: In the MA group, miR-3651 was upregulated while ATP6AP2 and SEC63 were downregulated, accompanied by higher butyl benzyl phthalate (BBP) exposure (all p<0.05). LgBBP was significantly associated with MA (OR=4.434; 95% CI: 1.772, 11.094; p=0.001; q=0.019), whereas ATP6AP2 showed only a borderline inverse association (OR=0.354; p=0.051). LgMEHP (mono(2-ethylhexyl) phthalate) showed a nominal positive association with miR-3651 (β=0.610; 95% CI: 0.090, 1.129; p=0.022; q=0.110). Exploratory quantile g-computation (qgcomp) weights showed LgMEHP (43.36% of positive weights) and LgBBP (31.74% of negative weights) as the largest weight components for miR-3651 and ATP6AP2, respectively. In vitro, BBP and MEHP increased miR-3651 but decreased ATP6AP2 and SEC63 (p<0.05). Overexpression of miR-3651 downregulated PLGF and VEGF-A while upregulating IL-6, IL-17 and IFN-γ. Additionally, both BBP and MEHP reduced VEGF-A levels, while MEHP increased IL-6 levels (p < 0.05).
CONCLUSION: This study shows that phthalate exposure is associated with miR-3651 upregulation and downregulation of ATP6AP2 and SEC63 in MA.