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1.
Environ Int ; 184: 108477, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38340406

RESUMEN

Nickel, a common environmental hazard, is a risk factor for craniosynostosis. However, the underlying biological mechanism remains unclear. Here, we found that early-life nickel exposure induced craniosynostosis in mice. In vitro, nickel promoted the osteogenic differentiation of human mesenchymal stem cells (hMSCs), and its osteogenic ability in vivo was confirmed by an ectopic osteogenesis model. Further mRNA sequencing showed that ERK1/2 signaling and FGFR2 were aberrantly activated. FGFR2 was identified as a key regulator of ERK1/2 signaling. By promoter methylation prediction and methylation-specific PCR (MSP) assays, we found that nickel induced hypomethylation in the promoter of FGFR2, which increased its binding affinity to the transcription factor Sp1. During pregnancy and postnatal stages, AZD4547 rescued nickel-induced craniosynostosis by inhibiting FGFR2 and ERK1/2. Compared with normal individuals, nickel levels were increased in the serum of individuals with craniosynostosis. Further logistic and RCS analyses showed that nickel was an independent risk factor for craniosynostosis with a nonlinear correlation. Mediated analysis showed that FGFR2 mediated 30.13% of the association between nickel and craniosynostosis risk. Collectively, we demonstrate that early-life nickel exposure triggers the hypomethylation of FGFR2 and its binding to Sp1, thereby promoting the osteogenic differentiation of hMSCs by ERK1/2 signaling, leading to craniosynostosis.


Asunto(s)
Craneosinostosis , Sistema de Señalización de MAP Quinasas , Femenino , Embarazo , Ratones , Humanos , Animales , Sistema de Señalización de MAP Quinasas/fisiología , Níquel/toxicidad , Osteogénesis , Craneosinostosis/genética , Transducción de Señal , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos
2.
Sci Total Environ ; 904: 166667, 2023 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-37652374

RESUMEN

Lead (Pb) is widely used in industrial and daily-use consumer products. Early-life exposure may increase the risk of lead-related heart problems in childhood. However, the effects of early-life lead exposure on fetal heart development and long-term cardiac outcomes are unknown. In this study, pregnant ICR mice were exposed to lead acetate trihydrate (50 mg/kg/d) via oral gavage from gestation day 1.5 until offspring weaning. Thereafter, the second hit model was established, two groups of offspring (4 weeks old) were either administered sterile saline or Angiotensin II (Ang II) for 4 weeks until euthanasia. We investigated lead-induced offspring heart damage from embryonic period to adulthood by echocardiographic analysis, pathological H&E staining, and ultrastructural examination, as well as mitochondrial function detection. The results showed early-life lead exposure predisposed offspring mice to decreased ejection fraction, increased left ventricular volume, accompanied by hypertrophy and dilation, cardiomyocyte sarcomere dysplasia, abnormal mitochondrial structure, mitochondrial dysfunction, and decreased expression of key sarcomeric and mitochondrial genes, rendering them more susceptible to cardiac hypertrophy, vascular wall thickening, cardiac fibrosis, apoptosis, and heart failure induced by Ang II infusion. This study elucidates early-life low dose lead exposure compromises cardiac development and exacerbates second hit-induced cardiac pathological responses in adulthood, which furnishes crucial scientific evidence pertaining to the cardiac toxicity and risk evaluation associated with early-life exposure to lead.


Asunto(s)
Cardiomegalia , Plomo , Humanos , Embarazo , Femenino , Ratones , Animales , Plomo/toxicidad , Plomo/metabolismo , Ratones Endogámicos ICR , Cardiomegalia/inducido químicamente , Cardiomegalia/genética , Cardiomegalia/metabolismo , Miocitos Cardíacos , Presión Sanguínea , Angiotensina II/farmacología , Angiotensina II/toxicidad
3.
BMC Med ; 20(1): 454, 2022 11 23.
Artículo en Inglés | MEDLINE | ID: mdl-36424578

RESUMEN

BACKGROUND: Previous studies have reported that maternal smoking during pregnancy and breastfeeding may affect the occurrence of hypertension, but whether early life factors modify the impact of the offspring's genetic risk on hypertension is still unknown. The aim of this study was to investigate the relationships among maternal smoking and breastfeeding with adult-onset hypertension and the modified impact of offspring genetic susceptibility. METHODS: This study included 437,185 participants from the UK Biobank who were initially free of hypertension and provided a prospective cohort of individuals aged 40 to 69 years. The association of maternal smoking during pregnancy and breastfeeding with hypertension was examined by using the Cox regression model. Then, a polygenic risk score (PRS) for hypertension was used to test the gene-environmental interaction on hypertension. RESULTS: During a median follow-up period of 8.7 years, a total of 68,148 cases of hypertension were identified in this study. The hazard ratios (HRs) and 95% confidence intervals (CIs) of hypertension for maternal smoking and breastfeeding were 1.11 (1.09, 1.13) and 0.96 (0.94, 0.98), respectively. However, no evidence of an interaction between maternal smoking and breastfeeding was observed. Across all levels of genetic risk, including high genetic risk, maternal smoking and nonbreastfeeding had higher hypertension hazards than nonmaternal smoking and breastfeeding, respectively. The adjusted HRs (95% CIs) of hypertension were 1.80 (1.73, 1.87) in those who had high genetic predisposition plus maternal smoking and 1.67 (1.60-1.74) in those with nonbreastfeeding and high genetic risk. There were significant additive interactions between maternal smoking or breastfeeding and genetic factors on the incidence of hypertension. CONCLUSIONS: Maternal smoking and nonbreastfeeding were associated with a higher risk of hypertension in adulthood and may attenuate the risk of hypertension related to genetic factors. These results suggested that adherence to nonmaternal smoking and breastfeeding was associated with a lower risk of hypertension among participants with all gradients of genetic risk.


Asunto(s)
Lactancia Materna , Hipertensión , Adulto , Embarazo , Femenino , Humanos , Estudios Prospectivos , Fumar/efectos adversos , Fumar/epidemiología , Hipertensión/epidemiología , Hipertensión/genética , Madres , Factores de Riesgo , Predisposición Genética a la Enfermedad
4.
Environ Sci Pollut Res Int ; 29(26): 39768-39776, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-35113370

RESUMEN

Evidence from previous studies has shown that exposure to cadmium (Cd) is associated with cardiovascular disease, kidney disease, and osteoporosis, but the effects of Cd on liver toxicity in adolescents are unclear. The data of 4411 adolescents who participated in the US The National Health and Nutrition Examination Survey (NHANES) during 1999-2016 was analyzed. Liver function was indicated by the levels of alanine aminotransferase (ALT) and aspartate amino transferase (AST). The associations between the levels of urinary Cd and liver function were evaluated using multivariate logistic regression models adjusted for covariates. The results showed that the odds ratios of ALT and AST in the highest quartiles of urinary Cd were 1.40 (95% confidence interval [CI], 1.07-1.82) and 1.64 (95% CI, 1.10-2.44), respectively, compared with the lowest quartiles, which were similar to using urinary creatinine as the covariate. We also found linear regression of associations of urinary Cd with elevated ALT and AST levels in boys. In addition, one augmented urinary Cd concentration unit (Log10) was associated with a 0.04-mg/dL increase in C-reactive protein and a 0.53-mg/dL decrease in HDL cholesterol in the fully adjusted model. Our results add novel evidence that exposure to Cd might be positively associated with indicators of liver injury, indicating the potential toxic effect of Cd exposure on the adolescent liver. Further confirmatory studies are needed.


Asunto(s)
Cadmio , Hígado , Adolescente , Alanina Transaminasa , Aspartato Aminotransferasas , Cadmio/toxicidad , Humanos , Masculino , Encuestas Nutricionales
5.
Ann Hepatol ; 26: 100558, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34653688

RESUMEN

INTRODUCTION AND OBJECTIVES: Gallbladder disease is a common disease with high prevalence. Majority of gallbladder disease is due to gallstone. Though genetics are believed to play a role in its pathogenesis, the contribution of environmental pressures in early life to the development of this disease in adulthood has not been ever investigated. This study aimed to clarify the risk of maternal smoking exposure in association with gallbladder disease in adulthood. The interaction of maternal smoking and own smoking during adulthood on this association was studied as well. PATIENTS AND METHODS: A total of 286,731 eligible participants from the UK Biobank population-based cohort were included. Multivariable Cox regression analysis were used to examine the HR and 95% CI with adjustment for covariates. RESULT: During a median of 8.8 years follow-up, 7110 incident cases of gallbladder disease including 6800 (95.6%) gallstone were identified. Maternal smoking was associated with increased risk of incident total gallbladder disease (HR = 1.13; 95%CI: 1.06 - 1.21; P = 0.0002) as well as gallstones (HR = 1.13; 95%CI: 1.06 -1.21; P = 0.0003) in adulthood. Compared with those who were neither exposed to maternal smoking nor own smoking, subjects adherence to no smoking during adulthood but having maternal smoking exposure still had increased risk of total gallbladder disease (HR = 1.21; 95%CI: 1.1-1.34, P=0.0001) and gallstones (HR = 1.21; 95%CI: 1.1-1.35, P=0.0001). CONCLUSION: The present study using large prospective cohort data from UK Biobank, for the first time, demonstrated maternal smoking exposure bringing elevated risk of incident total gallbladder disease/gallstone in adulthood.


Asunto(s)
Bancos de Muestras Biológicas/estadística & datos numéricos , Enfermedades de la Vesícula Biliar/etiología , Efectos Tardíos de la Exposición Prenatal/epidemiología , Medición de Riesgo/métodos , Fumar/efectos adversos , Femenino , Estudios de Seguimiento , Enfermedades de la Vesícula Biliar/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Morbilidad/tendencias , Embarazo , Estudios Prospectivos , Factores de Riesgo , Factores de Tiempo , Reino Unido/epidemiología
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