Cadmium inhibits placental trophoblast cell migration via miRNA regulation of the transforming growth factor beta (TGF-β) pathway

Brooks, Samira A.; Fry, Rebecca C.

doi:10.1016/j.fct.2017.07.059

Cited by 49 publications

(19 citation statements)

References 24 publications

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“…19 In addition, JEG3 cells have been a key model for understanding how environmental toxicants, such as inorganic arsenic, PFAS, and cadmium, impact placental function. 18,[20][21][22] Of importance, a large effort is currently underway by the U.S. Environmental Protection Agency (EPA) to reduce, refine, and replace animal testing for chemical safety research with in vitro assays. A key step towards this goal is understanding how in vitro conditions impact internal accumulation of toxic substances such as PFAS and, ultimately, affect the translational capacity of in vitro toxicological assessments.…”

mentioning

confidence: 99%

An assessment of serum‐dependent impacts on intracellular accumulation and genomic response of per‐ and polyfluoroalkyl substances in a placental trophoblast model

Bangma

Szilagyi

Blake

et al. 2020

Environmental Toxicology

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Per‐ and polyfluoroalkyl substances (PFAS), a class of environmental contaminants, have been detected in human placenta and cord blood. The mechanisms driving PFAS‐induced effects on the placenta and adverse pregnancy outcomes are not well understood. This study investigated the impact of perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and a replacement PFAS known as hexafluoropropylene oxide dimer acid (HFPO‐DA, tradename GenX) on placental trophoblasts in vitro. Several key factors were addressed. First, PFAS levels in cell culture reagents at baseline were quantified. Second, the role of supplemental media serum in intracellular accumulation of PFAS in a human trophoblast (JEG3) cell line was established. Finally, the impact of PFAS on the expression of 96 genes involved in proper placental function in JEG3 cells was evaluated. The results revealed that serum‐free media (SFM) contained no detectable PFAS. In contrast, fetal bovine serum‐supplemented media (SSM) contained PFNA, PFUdA, PFTrDA, and 6:2 FTS, but these PFAS were not detected internally in cells. Intracellular accumulation following 24 hr treatments was significantly higher when cultured in SFM compared to SSM for PFOS and PFOA, but not HFPO‐DA. Treatment with PFAS was associated with gene expression changes (n = 32) in pathways vital to placental function, including viability, syncytialization, inflammation, transport, and invasion/mesenchymal transition. Among the most robust PFAS‐associated changes were those observed in the known apoptosis‐related genes, BAD and BAX. These results suggest a complex relationship between PFAS, in vitro culture conditions, and altered expression of key genes necessary for proper placentation.

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confidence: 99%

An assessment of serum‐dependent impacts on intracellular accumulation and genomic response of per‐ and polyfluoroalkyl substances in a placental trophoblast model

Bangma

Szilagyi

Blake

et al. 2020

Environmental Toxicology

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“…Consequently, miRNAs have been proposed as biomarkers of Cd induced kidney injury (Fay et al, 2018). Furthermore, Cd exposure altered the expression of several miRNAs in human placenta and placental trophoblasts (Brooks et al, 2016;Brooks and Fry, 2017). This suggests that deregulation of miRNA-based mechanisms could be important in Cd pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…2A). Earlier studies have identified transcriptional alterations of miRNAs due to Cd exposure (Brooks et al, 2016;Brooks and Fry, 2017;Fay et al, 2018). However, systematic analyses of the differentially expressed miRNAs and their target genes have not been carried out thus far.…”

Section: Exposure Downregulates Mir-30 Family Mirnasmentioning

confidence: 99%

Cadmium exposure upregulates SNAIL through miR-30 repression in human lung epithelial cells

Tanwar

Zhang

Jagannathan

et al. 2019

Toxicology and Applied Pharmacology

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Cadmium (Cd) is a known human lung carcinogen. In addition, Cd exposure is associated with several lung diseases including emphysema, chronic obstructive pulmonary disease (COPD), asthma and fibrosis. Although earlier studies have identified several processes dysregulated by Cd exposure, the underlying mechanisms remain unclear. Here, we examined the transcriptome of lung epithelial cells exposed to Cd to understand the molecular basis of Cd-induced diseases. Computational analysis of the transcriptome predicted a significant number of Cd-upregulated genes to be targets of miR-30 family miRNAs. Experimental validation showed downregulation of all the miR-30 family members in Cd exposed cells. We found SNAIL, an EMT master regulator, to be the most upregulated among the miR-30 targets. Furthermore, we found decrease in the levels of epithelial marker E-cadherin (CDH1) and increase in the levels of mesenchymal markers, ZEB1 and vimentin. This suggested induction of EMT in Cd exposed cells. Luciferase reporter assays showed that miR-30 repressed SNAIL by directly targeting its 3′ UTR. Over expression of miR-30e and miR-30e mimics reduced Cd-induced SNAIL upregulation. Our results suggest that miR-30 negatively regulates SNAIL in lung epithelial cells and that Cd-induced downregulation of miR-30 relieves this repression, resulting in SNAIL upregulation and EMT induction. EMT plays a major role in many diseases associated with Cd exposure including fibrosis, COPD and cancer and metastasis. Therefore, our identification of miR-30 downregulation in Cd exposed cells and the consequent activation of SNAIL provides important mechanistic insights into lung diseases associated with Cd exposure.

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“…Until now, most studies focused on chemical exposures including cadmium [57], phthalates [58], arsenic [59], and endocrine disrupting chemicals [60] in association with placental miRNAs. Moreover, multiple studies confirm a role for miRNAs in the response to air pollution exposure in adults [61–63].…”

Section: Air Pollution-induced Placental Epigenetic Alterationsmentioning

confidence: 99%

Air pollution-induced placental alterations: an interplay of oxidative stress, epigenetics, and the aging phenotype?

et al. 2019

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According to the "Developmental Origins of Health and Disease" (DOHaD) concept, the early-life environment is a critical period for fetal programming. Given the epidemiological evidence that air pollution exposure during pregnancy adversely affects newborn outcomes such as birth weight and preterm birth, there is a need to pay attention to underlying modes of action to better understand not only these air pollution-induced early health effects but also its later-life consequences. In this review, we give an overview of air pollution-induced placental molecular alterations observed in the ENVIRONAGE birth cohort and evaluate the existing evidence. In general, we showed that prenatal exposure to air pollution is associated with nitrosative stress and epigenetic alterations in the placenta. Adversely affected CpG targets were involved in cellular processes including DNA repair, circadian rhythm, and energy metabolism. For miRNA expression, specific air pollution exposure windows were associated with altered miR-20a, miR-21, miR-146a, and miR-222 expression. Early-life aging markers including telomere length and mitochondrial DNA content are associated with air pollution exposure during pregnancy. Previously, we proposed the air pollution-induced telomere-mitochondrial aging hypothesis with a direct link between telomeres and mitochondria. Here, we extend this view with a potential co-interaction of different biological mechanisms on the level of placental oxidative stress, epigenetics, aging, and energy metabolism. Investigating the placenta is an opportunity for future research as it may help to understand the fundamental biology underpinning the DOHaD concept through the interactions between the underlying modes of action, prenatal environment, and disease risk in later life. To prevent lasting consequences from early-life exposures of air pollution, policy makers should get a basic understanding of biomolecular consequences and transgenerational risks.

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Cadmium inhibits placental trophoblast cell migration via miRNA regulation of the transforming growth factor beta (TGF-β) pathway

Abstract: Graphical Abstract

Cited by 49 publications

References 24 publications

An assessment of serum‐dependent impacts on intracellular accumulation and genomic response of per‐ and polyfluoroalkyl substances in a placental trophoblast model

An assessment of serum‐dependent impacts on intracellular accumulation and genomic response of per‐ and polyfluoroalkyl substances in a placental trophoblast model

Cadmium exposure upregulates SNAIL through miR-30 repression in human lung epithelial cells

Air pollution-induced placental alterations: an interplay of oxidative stress, epigenetics, and the aging phenotype?

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