Associations between prenatal exposure to cadmium and lead with neural tube defect risks are modified by single-nucleotide polymorphisms of fetal MTHFR and SOD2: a case–control study

Abstract

Background Prenatal exposure to heavy metals is implicated in the etiology of birth defects. We investigated whether concentrations of cadmium (Cd) and lead (Pb) in umbilical cord tissue are associated with risk for neural tube defects (NTDs) and whether selected genetic variants of the fetus modify their associations. Methods This study included 166 cases of NTD fetuses/newborns and 166 newborns without congenital malformations. Umbilical cord tissue was collected at birth or elective pregnancy termination. Cd and Pb concentrations were assessed by inductively coupled plasma-mass spectrometry, and 20 single-nucleotide polymorphisms (SNPs) in 9 genes were genotyped. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the risk for NTDs in association with metal concentrations or genotype using logistic regression. Multiplicative-scale interactions between the metals and genotypes on NTD risk were assessed with logistic regression, and additive-scale interactions were estimated with a non-linear mixed effects model. Results Higher concentrations of Cd were observed in the NTD group than in the control group, but no difference was found for Pb. Concentrations of Cd above the median level showed a risk effect, while the association between Pb and NTD risk was not significant in univariate analyses. The association of Cd was attenuated after adjusting for periconceptional folic acid supplementation. Fetuses with the AG and GG genotypes of rs4880 in SOD2 (superoxide dismutase 2) tended to have a lower risk, but fetuses with the CT and TT genotypes of rs1801133 in MTHFR (5,10-methylenetetrahydrofolatereductase) have a higher risk for NTDs when compared to their respective wild-type. rs4880 and Cd exhibited a multiplicative-scale interaction on NTD risk: the association between higher Cd and the risk for NTDs was increased by over fourfold in fetuses carrying the G allele [OR 4.43 (1.30–15.07)] compared to fetuses with the wild-type genotype. rs1801133 and Cd exposure showed an additive interaction, with a significant relative excess risk of interaction [RERI 0.64 (0.02–1.25)]. Conclusions Prenatal exposure to Cd may be a risk factor for NTDs, and the risk effect may be enhanced in fetuses who carry the G allele of rs4880 in SOD2 and T allele of rs1801133 in MTHFR.

Lack of Offspring Nrf2 Does Not Exacerbate the Detrimental Metabolic Outcomes Caused by In Utero PCB126 Exposure

“…To our knowledge, the present study is the first to report the developmental role of Nrf2 in PCB-induced toxicity in rodents. Previously, mice have been utilized to delineate the developmental role of Nrf2 in neural function and/or behavior in response to pharmaceutical ( 47 ) and recreational drugs ( 48 ), antioxidants ( 49 ), as well as heavy metals ( 49 ). Diet studies have been used to better understand the role of Nrf2 expression in obesity and diabetes.…”

Interacción de factores genéticos y ambientales en el metabolismo del ácido fólico y la patogénesis de defectos del tubo neural

“…Respecto a los contaminantes ambientales que presentan una relación con el riesgo de DNT, son los hidrocarburos aromáticos policíclicos (HAP) que ingresan al ambiente posterior a la combustión incompleta de biomasa (15), las mujeres gestantes expuestas a HAP tenían más bebés afectados por DNT (18). Estudios epidemiológicos han hallado la relación entre la exposición prenatal a cadmio y plomo y los DNT, en donde, el efecto de riesgo de DNT puede aumentar en los fetos que presentan polimorfismos del gen MTHFR (19). Las concentraciones de cadmio mayores a 1,16 ng/g mostraron un efecto de riesgo de DNT; sin embargo, se Brazilian Journal of Health Review, Curitiba, v. 6, n. 1, p.3585-3599, jan./feb., 2023 comprobó que la asociación de cadmio se atenuó después de ajustar por la suplementación con ácido fólico periconcepcional (19).…”

“…Estudios epidemiológicos han hallado la relación entre la exposición prenatal a cadmio y plomo y los DNT, en donde, el efecto de riesgo de DNT puede aumentar en los fetos que presentan polimorfismos del gen MTHFR (19). Las concentraciones de cadmio mayores a 1,16 ng/g mostraron un efecto de riesgo de DNT; sin embargo, se Brazilian Journal of Health Review, Curitiba, v. 6, n. 1, p.3585-3599, jan./feb., 2023 comprobó que la asociación de cadmio se atenuó después de ajustar por la suplementación con ácido fólico periconcepcional (19). Dentro de los factores ambientales también se encuentran involucradas ciertas enfermedades metabólicas que afectan a la madre, lo que permite un aumento del riesgo de DNT (1).…”

“…De igual modo, otra de las interacciones investigadas fue con los hidrocarburos aromáticos policíclicos (HAP), donde Langlois, et al (18), evidenció la asociación de los DNT con los HAP en mujeres con peso bajo o normal. Así mismo, Liu, et al (19), señaló que la asociación entre Cd y el riesgo de DNT aumentó más de cuatro veces en los fetos que portaban el polimorfismo SOD2 rs4880. Finalmente, Padula, et al (39), al investigar sobre la exposición a la contaminación del aire y el riesgo de espina bífida, indicó que la exposición al óxido nítrico (NO) y la variante de CYP1A2 (rs762551) se asocia con un riesgo 5 veces mayor de este DNT.…”

Correction to: Associations between prenatal exposure to cadmium and lead with neural tube defect risks are modified by single-nucleotide polymorphisms of fetal MTHFR and SOD2: a case–control study

“…Following the publication of the original article [ 1 ], the author reported an error in the affiliation list of Dr. Lei Jin and the address for the correspondence. Dr. Jins’ affiliation should only be 1 and 2, and the address for both corresponding authors should be Institute of Reproductive and Child Health/Key Laboratory of Reproductive Health, National Health Commission of the People’s Republic of China, Peking University, Beijing, China.…”