Sex-specific difference in placental inflammatory transcriptional biomarkers of maternal phthalate exposure: a prospective cohort study

Wang, Jianqing; Hu, Yabin; Gao, Hui; Sheng, Jie; Huang, Kun; Zhang, Yunwei; Mao, Leijing; Zhou, Shusheng; Cai, Xiaopan; Zhang, Liangjian; Wang, Sufang; Hao, Jiahu; Yang, Liqi; Tao, Fangbiao

doi:10.1038/s41370-020-0200-z

Cited by 29 publications

(16 citation statements)

References 51 publications

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“…However, this finding does not necessarily imply that pregnancies with female fetuses are selectively vulnerable to PAE, since we also observed PAE-linked changes in maternal miRNA profiles in pregnancies with both male and female fetuses following bootstrap-based assessments of effect size. A number of studies have shown that male fetal and postnatal development can also be uniquely sensitive to altered maternal environments due to drug and toxin exposures [6,23,25,55,65]. However, our analysis does suggest that the toxic effects of PAE may be mediated by different mechanisms in male and female fetuses.…”

Section: Discussionmentioning

confidence: 57%

Association between fetal sex and maternal plasma microRNA responses to prenatal alcohol exposure: evidence from a birth outcome-stratified cohort

et al. 2020

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Most persons with fetal alcohol spectrum disorders (FASDs) remain undiagnosed or are diagnosed in later life. To address the need for earlier diagnosis, we previously assessed miRNAs in the blood plasma of pregnant women who were classified as unexposed to alcohol (UE), heavily exposed with affected infants (HEa), or heavily exposed with apparently unaffected infants (HEua). We reported that maternal miRNAs predicted FASD-related growth and psychomotor deficits in infants. Here, we assessed whether fetal sex influenced alterations in maternal circulating miRNAs following prenatal alcohol exposure (PAE). To overcome the loss of statistical power due to disaggregating maternal samples by fetal sex, we adapted a strategy of iterative bootstrap resampling with replacement to assess the stability of statistical parameter estimates. Bootstrap estimates of parametric and effect size tests identified male and female fetal sex-associated maternal miRNA responses to PAE that were not observed in the aggregated sample. Additionally, we observed, in HEa mothers of female, but not male fetuses, a network of co-secreted miRNAs whose expression was linked to miRNAs encoded on the X-chromosome. Interestingly, the number of significant miRNA correlations for the HEua group mothers with female fetuses was intermediate between HEa and UE mothers at mid-pregnancy, but more similar to UE mothers by the end of pregnancy. Collectively, these data show that fetal sex predicts maternal circulating miRNA adaptations, a critical consideration when adopting maternal miRNAs as diagnostic biomarkers. Moreover, a maternal co-secretion network, predominantly in pregnancies with female fetuses, emerged as an index of risk for adverse birth outcomes due to PAE.

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Section: Discussionmentioning

confidence: 57%

Association between fetal sex and maternal plasma microRNA responses to prenatal alcohol exposure: evidence from a birth outcome-stratified cohort

et al. 2020

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“…They promote inflammatory response (Wang et al, 2014) and may contribute to the establishment of lesions such as human prostate tumors (Fang et al, 2013). CD68 is a type I transmembrane glycoprotein and is a known pan‐macrophage marker (Kim et al, 2020) that can be utilized to recognize both tumoricidal M1 (Wang et al, 2020) and anti‐inflammatory M2 macrophages (He et al, 2014; Barbosa et al, 2015). This may explain a higher rate of macrophages/area obtained by using the CD68 marker, which may indicate not only the presence of M1 but M2 in the prostate.…”

Section: Discussionmentioning

confidence: 99%

Ethinylestradiol and its effects on the macrophages in the prostate of adult and senile gerbils

Castro

Falleiros‐Júnior

Zucão

et al. 2020

Cell Biology International

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Prenatal and neonatal exposure to estrogenic compounds, such as ethinylestradiol (EE), promotes a variety of developmental disorders, including malformations and alterations in the morphology of glands, such as the prostate gland. Therefore, the aim of this study was to evaluate the morphological effects of neonatal exposure to EE on prostatic tissue and on the identification and quantification of gerbil gland macrophages in adult and senile Mongolian gerbils. The animals were exposed to EE (10 μg/kg/day) and to the vehicle, mineral oil (100 μL) (control group) during the first 10 days of postnatal life (lactation period). Adult gerbils were euthanized at 120 days and senile gerbils at 12 months of age. Our findings permitted verification of the presence of areas with proliferative foci in the prostate glandular portions in the adult and senile animals exposed to EE. There was also an increase in macrophages in the prostate tissue of adult and senile gerbils; these cell types alter the stromal microenvironment and possibly modify the interactions between the epithelium and stroma. Neonatal exposure to EE changes the pattern of prostatic development, leading to alterations in the arrangement of cells, including macrophages, and may be related to the onset of proliferative disorders in the prostate of adult gerbils and during aging.

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“…After the placenta was delivered, it was rinsed with normal saline. In an area without hemorrhage, infarction, or calcification, slices of <0.5 cm were cut in the sagittal direction with scissors, placed in a cryopreservation tube with RNA, and stored at −80 °C (Wang et al 2020). Using TRI reagent (MRC Inc., Cincinnati, OH, USA), total RNA was isolated according to the manufacturer's protocol.…”

Section: Placental Inflammatory Biomarkersmentioning

confidence: 99%

“…The first trimester of pregnancy was the most vulnerable period in terms of neurotoxicity due to phthalate exposure (Zhu et al 2020a). We also have investigated the effects of prenatal phthalate exposure on placental inflammation (Wang et al 2020). We primarily observed that metabolites of dibutyl phthalate (DBP), butyl benzyl phthalate (BBzP), and di(2-ethylhexyl) phthalate (DEHP) were associated with an increase in the proinflammatory cytokine IL-6 and the classically activated macrophage (M1) biomarker CD68 (Wang et al 2020).…”

Section: Introductionmentioning

confidence: 99%

“…We also have investigated the effects of prenatal phthalate exposure on placental inflammation (Wang et al 2020). We primarily observed that metabolites of dibutyl phthalate (DBP), butyl benzyl phthalate (BBzP), and di(2-ethylhexyl) phthalate (DEHP) were associated with an increase in the proinflammatory cytokine IL-6 and the classically activated macrophage (M1) biomarker CD68 (Wang et al 2020). Therefore, nested on the MABC study, we further explored the impact of cumulative exposure to DBP, BBzP, and DEHP during early pregnancy on placental inflammation (such as IL-6 and CD68) and preschooler cognitive development and to determine whether changes in placental inflammation could mediate the associat i o n s b e t w e e n p h t h a l a t e e x p o s u r e a n d c h i l d neurodevelopment.…”

Section: Introductionmentioning

confidence: 99%

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Sex-specific mediation of placental inflammatory biomarkers in the effects of prenatal phthalate coexposure on preschooler cognitive development

Gao

Tong

Zhu

et al. 2021

Environ Sci Pollut Res

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The objective of this study is to investigate the mediating effect of placental inflammatory biomarkers on the relationship between prenatal phthalate coexposure and cognitive development in preschoolers. A subgroup of 1660 mother-child pairs from the Ma'anshan Birth Cohort study were included. We measured the levels of phthalate metabolites of dibutyl phthalate (DBP), butyl benzyl phthalate (BBzP), and di (2-ethylhexyl) phthalate (DEHP) in all the women included in the study from three urine samples collected in each of the trimesters. A potency-weighted sum of coexposure to DBP, BBzP, and DEHP (indicator: ∑PAE) was calculated. The mRNA of the proinflammatory cytokine IL-6 and the classically activated macrophage (M1) biomarker CD68 was analyzed using placental tissues. The Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition-Chinese was used to evaluate the full-scale intelligence quotient (FSIQ) of children aged 2.5-6 years. Average ∑PAEs and ∑PAEs in each trimester were associated with IL-6 and CD68. ∑PAE in the first trimester was positively associated with IL-6 (β = 0.11, 95% CIs = 0.03-0.19) and CD68 (β = 0.16, 95% CIs = 0.04-0.28), and negatively associated with FSIQ (β =−0.06, 95% CIs = −0.11 to −0.02), verbal comprehension (β =−0.06, 95% CIs = −0.11 to −0.01), and processing speed (β =−0.07, 95% CIs = −0.12 to −0.01). Additionally, sex discrepancies were observed for the mediating effects of placental inflammation on the relationships between ∑PAE and children's cognitive development. For instance, the association between ∑PAE in early pregnancy and FSIQ was partially mediated by IL-6 (estimated proportion mediated: 21.85%) and CD68 (estimated proportion mediated: 16.2%). Gender-specific associations and trimester-specific relationships of prenatal multiple phthalate coexposure were revealed. ∑PAE in the first trimester of pregnancy was associated with increased of placental inflammation, and a decrease in preschoolers' cognitive development. In boys, placental IL-6 and CD68 elevation resulting from phthalates might be potential mechanisms of poor cognitive development.

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Sex-specific difference in placental inflammatory transcriptional biomarkers of maternal phthalate exposure: a prospective cohort study

Cited by 29 publications

References 51 publications

Association between fetal sex and maternal plasma microRNA responses to prenatal alcohol exposure: evidence from a birth outcome-stratified cohort

Association between fetal sex and maternal plasma microRNA responses to prenatal alcohol exposure: evidence from a birth outcome-stratified cohort

Ethinylestradiol and its effects on the macrophages in the prostate of adult and senile gerbils

Sex-specific mediation of placental inflammatory biomarkers in the effects of prenatal phthalate coexposure on preschooler cognitive development

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