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Previous epidemiologic research has shown that phthalate exposure in pregnant women is related to adverse birth outcomes in a sex-specific manner. However, the biological mechanism of phthalate exposure that causes these birth outcomes remains poorly defined. In this research, we investigated the association between phthalate exposure and placental oxidative stress in a large population-based cohort study, aiming to initially explore the relationship between phthalate exposure and gene expression in placental oxidative stress in a sex-specific manner. Quantitative PCR was performed to measure the expression of placental inflammatory mRNAs (HO-1, HIF1α, and GRP78) in 2469 placentae. The multiple linear regression models were used to investigate the associations between mRNA and urinary phthalate monoesters. Phthalate metabolites monomethyl phthalate (MMP) and mono-n-butyl phthalate (MBP) were positively correlated with higher HIF1α expression in placentae of male fetuses (p <.05). Mono-benzyl phthalate (MBzP) increased the expression of HO-1, HIF1α, and GRP78 in placentae of male fetuses, and mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) up-regulated the expression of HIF1α and GRP78. Additionally, mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) was negatively correlated with HO-1, HIF1α, and GRP78 in placentae of female fetuses. Maternal phthalate exposure was associated with oxidative stress variations in placental tissues. The associations were closer in the placentas of male fetuses than in that of female ones. The placenta oxidative stress is worth further investigation as a potential mediator of maternal exposure-induced disease risk in children. [ABSTRACT FROM AUTHOR]

• This study is the first large-sample prospective cohort study to examine the association between placental inflammatory cytokines mRNA expression and preschoolers' behavioral problems. • In preschool boys, a positive association between placental pro-inflammatory chemokines IL-8 mRNA levels and CBCL scores on anxious/depressed problems, aggressive behaviors, externalizing problems and total problems is observed. • In preschool girls, medium levels of pro-inflammatory cytokines (CRP, IL-6, IL-1β) seems to be associated with a decreased risk of some behavioral problems (emotionally reactive problems, externalizing problems, withdrawal) compared to high or low levels. • For anti-inflammatory cytokines, medium levels of IL-4 are found to be associated with a low risk of externalizing problems in preschool girls and medium levels of IL-10 were related to a low risk of internalizing problems in preschool boys, compared to low levels. Placental inflammation may contribute to brain abnormalities and childhood neuropsychiatric disorders, but limited knowledge is available on the association of placental inflammatory cytokine levels and offspring's behavioral development. This study aimed to examine the sex-specific association between placental inflammatory cytokine mRNA expression and preschoolers' behavioral development. 3474 pregnant women were recruited as the initial study population in the Ma'anshan birth cohort (MABC) study. Placentas (n = 2519) were collected during childbirth, and the mRNA expression of IL-8, IL-1β, CRP, TNF-α, IL-6, IL-10, and IL-4 was assessed. The Child Behavior Checklist 1.5–5 (CBCL 1.5–5) was used to assess children's behavioral development at 4 years old. A T-score ≥ 60 on summary scales or a score ≥ 65 on syndrome scales was regarded as the borderline clinical range. Multiple linear regression models and binary logistic regression models were applied to explore the sex-specific associations between placental inflammatory cytokines mRNA transcript levels and preschoolers' behavioral development. Sex-specific associations between placental inflammatory cytokines mRNA expression and preschoolers' behavioral development were observed. There was a positive association between IL-8 and CBCL scores for boys on anxious/depressed problems, aggressive behaviors, externalizing problems and total problems. Logistic regression models showed that high levels of IL-8 were associated with a higher risk of girls' emotionally reactive problems and sleep problems compared to low/medium levels. High TNF-α was correlated with increased sleep problem scores in boys, and medium TNF-α (vs. low levels) was associated with an increased risk of girls' externalizing problems. Medium levels of CRP, IL-1β, and IL-6 were found to be associated with a decreased risk of girls' behavioral problems compared to low/high levels. For anti-inflammatory cytokines, medium IL-10 and IL-4 (vs. low levels) were observed to be associated with a lower risk of internalizing problems in boys and externalizing problems in girls, respectively. High IL-10 was correlated with decreased attention problem scores in boys. This study indicates that placental inflammatory cytokine mRNA expression of IL-8, CRP, TNF-α, IL-1β, IL-4 and IL-10 may be associated with preschoolers' behavioral development in a sex-specific manner. [ABSTRACT FROM AUTHOR]

Thallium (Tl), a ubiquitous environmental toxicant, can cross the placental barrier during pregnancy. However, the effects of prenatal Tl exposure on placental function are currently unclear. Based on the Ma'anshan Birth Cohort study, we examined whether long-term prenatal Tl exposure was associated with placental inflammation. Tl concentrations were quantified in serum samples (n = 7050) from 2515 pregnancy during each trimester, placental inflammatory cytokine mRNA expression was assessed in 2519 placenta tissues. Geometric mean values of serum Tl concentrations were 63.57, 63.63 and 48.71 ng/L for the first, second and third trimesters, respectively. After adjustment for potential confounders, serum Tl concentration was positively associated with CD68 (β: 0.30; 95% CI: 0.05, 0.56) in the first trimester and TNF-α (β: 0.12; 95% CI: 0.01, 0.23), IL-6 (β: 0.15; 95% CI: 0.05, 0.25) and CD68 (β: 0.25; 95% CI: 0.10, 0.39) in the third trimester, however was negatively associated with IL-4 (β: −0.21; 95% CI: −0.41, −0.01) and CD206 (β: −0.23; 95% CI: −0.45, −0.02) in the first trimester. Repeated measures analysis showed that TNF-α, IL-6 and CD68 increased by 0.11 (95% CI: 0.01, 0.21), 0.12 (0.15, 95% CI: 0.05, 0.25), 0.22 (95% CI: 0.10, 0.39), respectively, with each 1ln-transformed Tl increase in total samples. Gender-specific analyses revealed that these associations were largely driven by male offspring. In addition, immunohistochemistry revealed that nuclear NF-κB p65 expression increased in placenta tissue. The results of this prospective cohort study provide longitudinal evidence that prenatal Tl exposure induces a placental inflammatory response in the Chinese population. Image 1 • We measured 11 inflammatory cytokine mRNAs expression to observe local immune activation in the placenta. • Elevated Tl concentrations were associated with increased placental TNF-α, IL6 and CD68 mRNA expression in longitudinal analysis. • Our findings suggest that prenatal Tl exposure may induce the placenta inflammation response via NF-κB activation. [ABSTRACT FROM AUTHOR]