International Journal of Molecular Sciences

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20 pages, 2150 KiB

Open AccessArticle

Adult-Onset Transcriptomic Effects of Developmental Exposure to Benzene in Zebrafish (Danio rerio): Evaluating a Volatile Organic Compound of Concern

by Mackenzie L. Connell, Chia-Chen Wu, Jessica R. Blount, Alex Haimbaugh, Emily K. Kintzele, Dayita Banerjee, Bridget B. Baker and Tracie R. Baker

Int. J. Mol. Sci. 2023, 24(22), 16212; https://doi.org/10.3390/ijms242216212 - 11 Nov 2023

Cited by 1 | Viewed by 1427

Abstract

Urban environments are afflicted by mixtures of anthropogenic volatile organic compounds (VOCs). VOC sources that drive human exposure include vehicle exhaust, industrial emissions, and oil spillage. The highly volatile VOC benzene has been linked to adverse health outcomes. However, few studies have focused [...] Read more.

Urban environments are afflicted by mixtures of anthropogenic volatile organic compounds (VOCs). VOC sources that drive human exposure include vehicle exhaust, industrial emissions, and oil spillage. The highly volatile VOC benzene has been linked to adverse health outcomes. However, few studies have focused on the later-in-life effects of low-level benzene exposure during the susceptible window of early development. Transcriptomic responses during embryogenesis have potential long-term consequences at levels equal to or lower than 1 ppm, therefore justifying the analysis of adult zebrafish that were exposed during early development. Previously, we identified transcriptomic alteration following controlled VOC exposures to 0.1 or 1 ppm benzene during the first five days of embryogenesis using a zebrafish model. In this study, we evaluated the adult-onset transcriptomic responses to this low-level benzene embryogenesis exposure (n = 20/treatment). We identified key genes, including col1a2 and evi5b, that were differentially expressed in adult zebrafish in both concentrations. Some DEGs overlapped at the larval and adult stages, specifically nfkbiaa, mecr, and reep1. The observed transcriptomic results suggest dose- and sex-dependent changes, with the highest impact of benzene exposure to be on cancer outcomes, endocrine system disorders, reproductive success, neurodevelopment, neurological disease, and associated pathways. Due to molecular pathways being highly conserved between zebrafish and mammals, developmentally exposed adult zebrafish transcriptomics is an important endpoint for providing insight into the long term-effects of VOCs on human health and disease. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Reproductive and Developmental Toxicology)

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19 pages, 1966 KiB

Open AccessArticle

Prenatal Metal Exposure Alters the Placental Proteome in a Sex-Dependent Manner in Extremely Low Gestational Age Newborns: Links to Gestational Age

by Anastasia N. Freedman, Kyle Roell, Eiona Engwall, Catherine Bulka, Karl C. K. Kuban, Laura Herring, Christina A. Mills, Patrick J. Parsons, Aubrey Galusha, Thomas Michael O’Shea and Rebecca C. Fry

Int. J. Mol. Sci. 2023, 24(19), 14977; https://doi.org/10.3390/ijms241914977 - 7 Oct 2023

Cited by 1 | Viewed by 1376

Abstract

Prenatal exposure to toxic metals is associated with altered placental function and adverse infant and child health outcomes. Adverse outcomes include those that are observed at the time of birth, such as low birthweight, as well as those that arise later in life, [...] Read more.

Prenatal exposure to toxic metals is associated with altered placental function and adverse infant and child health outcomes. Adverse outcomes include those that are observed at the time of birth, such as low birthweight, as well as those that arise later in life, such as neurological impairment. It is often the case that these adverse outcomes show sex-specific responses in relation to toxicant exposures. While the precise molecular mechanisms linking in utero toxic metal exposures with later-in-life health are unknown, placental inflammation is posited to play a critical role. Here, we sought to understand whether in utero metal exposure is associated with alterations in the expression of the placental proteome by identifying metal associated proteins (MAPs). Within the Extremely Low Gestational Age Newborns (ELGAN) cohort (n = 230), placental and umbilical cord tissue samples were collected at birth. Arsenic (As), cadmium (Cd), lead (Pb), selenium (Se), and manganese (Mn) concentrations were measured in umbilical cord tissue samples via ICP-MS/MS. Protein expression was examined in placental samples using an LC-MS/MS-based, global, untargeted proteomics analysis measuring more than 3400 proteins. MAPs were then evaluated for associations with pregnancy and neonatal outcomes, including placental weight and gestational age. We hypothesized that metal levels would be positively associated with the altered expression of inflammation/immune-associated pathways and that sex-specific patterns of metal-associated placental protein expression would be observed. Sex-specific analyses identified 89 unique MAPs expressed in female placentas and 41 unique MAPs expressed in male placentas. Notably, many of the female-associated MAPs are known to be involved in immune-related processes, while the male-associated MAPs are associated with intracellular transport and cell localization. Further, several MAPs were significantly associated with gestational age in males and females and placental weight in males. These data highlight the linkage between prenatal metal exposure and an altered placental proteome, with implications for altering the trajectory of fetal development. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Reproductive and Developmental Toxicology)

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17 pages, 3646 KiB

Open AccessArticle

Restoring Angiotensin Type 2 Receptor Function Reverses PFOS-Induced Vascular Hyper-Reactivity and Hypertension in Pregnancy

by Sri Vidya Dangudubiyyam, Bradley Bosse, Pankaj Yadav, Ruolin Song, Alissa Hofmann, Jay S. Mishra and Sathish Kumar

Int. J. Mol. Sci. 2023, 24(18), 14180; https://doi.org/10.3390/ijms241814180 - 16 Sep 2023

Cited by 1 | Viewed by 1150

Abstract

Perfluorooctane sulfonic acid (PFOS) exposure during pregnancy induces hypertension with decreased vasodilatory angiotensin type-2 receptor (AT2R) expression and impaired vascular reactivity and fetal weights. We hypothesized that AT2R activation restores the AT1R/AT2R balance and reverses gestational hypertension by improving vascular mechanisms. Pregnant Sprague-Dawley [...] Read more.

Perfluorooctane sulfonic acid (PFOS) exposure during pregnancy induces hypertension with decreased vasodilatory angiotensin type-2 receptor (AT2R) expression and impaired vascular reactivity and fetal weights. We hypothesized that AT2R activation restores the AT1R/AT2R balance and reverses gestational hypertension by improving vascular mechanisms. Pregnant Sprague-Dawley rats were exposed to PFOS through drinking water (50 μg/mL) from gestation day (GD) 4–20. Controls received drinking water with no detectable PFOS. Control and PFOS-exposed rats were treated with AT2R agonist Compound 21 (C21; 0.3 mg/kg/day, SC) from GD 15–20. In PFOS dams, blood pressure was higher, blood flow in the uterine artery was reduced, and C21 reversed these to control levels. C21 mitigated the heightened contraction response to Ang II and enhanced endothelium-dependent vasorelaxation in uterine arteries of PFOS dams. The observed vascular effects of C21 were correlated with reduced AT1R levels and increased AT2R and eNOS protein levels. C21 also increased plasma bradykinin production in PFOS dams and attenuated the fetoplacental growth restriction. These data suggest that C21 improves the PFOS-induced maternal vascular dysfunction and blood flow to the fetoplacental unit, providing preclinical evidence to support that AT2R activation may be an important target for preventing or treating PFOS-induced adverse maternal and fetal outcomes. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Reproductive and Developmental Toxicology)

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15 pages, 3602 KiB

Open AccessArticle

Investigation of the Effects of Metallic Nanoparticles on Fertility Outcomes and Endocrine Modification of the Hypothalamic-Pituitary-Gonadal Axis

by Miguel A. Sogorb, Héctor Candela, Jorge Estévez and Eugenio Vilanova

Int. J. Mol. Sci. 2023, 24(14), 11687; https://doi.org/10.3390/ijms241411687 - 20 Jul 2023

Cited by 1 | Viewed by 1441

Abstract

Nanotechnology is a very disruptive twenty-first-century revolution that will allow social and economic welfare to increase although it also involves a significant human exposure to nanoparticles. The aim of the present study was to contribute to the elucidation on whether metallic nanoparticles have [...] Read more.

Nanotechnology is a very disruptive twenty-first-century revolution that will allow social and economic welfare to increase although it also involves a significant human exposure to nanoparticles. The aim of the present study was to contribute to the elucidation on whether metallic nanoparticles have a potential to induce fertility impairments. Regulatory studies that observed official OECD guidelines 415, 416 and 422 have failed to detect any fertility alterations caused by nanoparticle exposure. However, the scientific literature provides evidence that some nanoparticles may cause gonad impairments although the actual impact on fertility remains uncertain. This aim of the present study is to revisit the previously published RNAseq studies by analyzing the effects of several nanoparticles on the transcriptome of T98G human glioblastoma cells given that glial cells are known to play a pivotal role in the regulation of gonadotropin releasing hormone neurons. We found evidence that nanoparticles impair the gonadotropin releasing hormone receptor pathway and several related biological process like, among others, the cellular response to follicular stimulating hormone, cellular response to gonadotropin stimulus, cellular response to hormone stimulus, response to steroid hormone, ovulation cycle and response to estradiol. We propose that nanoparticles interfere with the ability of glial cells to regulate gonadotropin-releasing hormone neurons and, subsequently, the hypothalamic-pituitary-gonadal axis, potentially leading to fertility impairments. To our knowledge, this is the first proposal of a mode of action based on endocrine disruption for explaining the possible effects of nanoparticles on fertility. Whether these finding can be extended to other types of nanoparticles requires further investigation. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Reproductive and Developmental Toxicology)

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14 pages, 2788 KiB

Open AccessArticle

Transcriptome Analysis of the Developmental Effects of Bisphenol F Exposure in Chinese Medaka (Oryzias sinensis)

by Zhiying Liang, Yafen Guo, Duan Pi, Xiang Li, Bingying Li, Yongsi Huang, Xiaohong Song, Ramji Kumar Bhandari and Xuegeng Wang

Int. J. Mol. Sci. 2023, 24(13), 10898; https://doi.org/10.3390/ijms241310898 - 30 Jun 2023

Cited by 1 | Viewed by 1687

Abstract

Bisphenol F (BPF) has been used in the syntheses of polymers, which are widely used in coatings, varnishes, adhesives, and other plastics. During the past decades, BPF contamination in the aquatic environment has dramatically increased due to its release from manmade products. Concerns [...] Read more.

Bisphenol F (BPF) has been used in the syntheses of polymers, which are widely used in coatings, varnishes, adhesives, and other plastics. During the past decades, BPF contamination in the aquatic environment has dramatically increased due to its release from manmade products. Concerns have driven much attention to whether it may adversely impact aquatic lives or human beings. The present study performed an acute toxic exposure experiment and a 15 d developmental exposure of BPF at environmental concentrations (20, 200, and 2000 ng/L) using Chinese medaka (Oryzias sinensis). In the acute toxic exposure, the LC₅₀ of BPF to Chinese medaka is 87.90 mg/L at 96 h. Developmental exposure induced a significant increase in the frequency of larvae with abnormalities in the 2000 ng/L BPF group compared to the control group. Transcriptomic analysis of the whole larvae revealed 565 up-regulated and 493 down-regulated genes in the 2000 ng/L BPF exposure group. Analysis of gene ontology and KEGG pathways enrichments indicated endocrine disorders to be associated with BPF-induced developmental toxicity. The present results suggest that BPF is developmentally toxic at 2000 ng/L concentration in Chinese medaka and causes endocrine-related aberrations in the transcriptional network of genes. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Reproductive and Developmental Toxicology)

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20 pages, 5710 KiB

Open AccessArticle

Characterising the Effect of Wnt/β-Catenin Signalling on Melanocyte Development and Patterning: Insights from Zebrafish (Danio rerio)

by Praneeth Silva and Devi Atukorallaya

Int. J. Mol. Sci. 2023, 24(13), 10692; https://doi.org/10.3390/ijms241310692 - 27 Jun 2023

Cited by 1 | Viewed by 1527

Abstract

Zebrafish (Danio rerio) is a well-established model organism for studying melanocyte biology due to its remarkable similarity to humans. The Wnt signalling pathway is a conserved signal transduction pathway that plays a crucial role in embryonic development and regulates many aspects [...] Read more.

Zebrafish (Danio rerio) is a well-established model organism for studying melanocyte biology due to its remarkable similarity to humans. The Wnt signalling pathway is a conserved signal transduction pathway that plays a crucial role in embryonic development and regulates many aspects of the melanocyte lineage. Our study was designed to investigate the effect of Wnt signalling activity on zebrafish melanocyte development and patterning. Stereo-microscopic examinations were used to screen for changes in melanocyte count, specific phenotypic differences, and distribution in zebrafish, while microscopic software tools were used to analyse the differences in pigment dispersion of melanocytes exposed to LiCl (Wnt enhancer) and W-C59 (Wnt inhibitor). Samples exposed to W-C59 showed low melanocyte densities and defects in melanocyte phenotype and patterning, whereas LiCl exposure demonstrated a stimulatory effect on most aspects of melanocyte development. Our study demonstrates the crucial role of Wnt signalling in melanocyte lineage and emphasises the importance of a balanced Wnt signalling level for proper melanocyte development and patterning. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Reproductive and Developmental Toxicology)

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18 pages, 3803 KiB

Open AccessArticle

Antioxidant Supplementation Alleviates Mercury-Induced Cytotoxicity and Restores the Implantation-Related Functions of Primary Human Endometrial Cells

by Andrea Palomar, Alicia Quiñonero, Yassmin Medina-Laver, Roberto Gonzalez-Martin, Silvia Pérez-Debén, Pilar Alama and Francisco Domínguez

Int. J. Mol. Sci. 2023, 24(10), 8799; https://doi.org/10.3390/ijms24108799 - 15 May 2023

Viewed by 1439

Abstract

Mercury (Hg) cytotoxicity, which is largely mediated through oxidative stress (OS), can be relieved with antioxidants. Thus, we aimed to study the effects of Hg alone or in combination with 5 nM N-Acetyl-L-cysteine (NAC) on the primary endometrial cells’ viability and function. Primary [...] Read more.

Mercury (Hg) cytotoxicity, which is largely mediated through oxidative stress (OS), can be relieved with antioxidants. Thus, we aimed to study the effects of Hg alone or in combination with 5 nM N-Acetyl-L-cysteine (NAC) on the primary endometrial cells’ viability and function. Primary human endometrial epithelial cells (hEnEC) and stromal cells (hEnSC) were isolated from 44 endometrial biopsies obtained from healthy donors. The viability of treated endometrial and JEG-3 trophoblast cells was evaluated via tetrazolium salt metabolism. Cell death and DNA integrity were quantified following annexin V and TUNEL staining, while the reactive oxygen species (ROS) levels were quantified following DCFDA staining. Decidualization was assessed through secreted prolactin and the insulin-like growth factor-binding protein 1 (IGFBP1) in cultured media. JEG-3 spheroids were co-cultured with the hEnEC and decidual hEnSC to assess trophoblast adhesion and outgrowth on the decidual stroma, respectively. Hg compromised cell viability and amplified ROS production in trophoblast and endometrial cells and exacerbated cell death and DNA damage in trophoblast cells, impairing trophoblast adhesion and outgrowth. NAC supplementation significantly restored cell viability, trophoblast adhesion, and outgrowth. As these effects were accompanied by the significant decline in ROS production, our findings originally describe how implantation-related endometrial cell functions are restored in Hg-treated primary human endometrial co-cultures by antioxidant supplementation. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Reproductive and Developmental Toxicology)

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15 pages, 4796 KiB

Open AccessArticle

Cyanidin-3-O-Glucoside Rescues Zearalenone-Induced Apoptosis via the ITGA7-PI3K-AKT Signaling Pathway in Porcine Ovarian Granulosa Cells

by Xiuxiu Li, Jingya Wang, Fali Zhang, Mubin Yu, Ning Zuo, Lan Li, Jinghe Tan and Wei Shen

Int. J. Mol. Sci. 2023, 24(5), 4441; https://doi.org/10.3390/ijms24054441 - 23 Feb 2023

Cited by 4 | Viewed by 1951

Abstract

Zearalenone (ZEN) is an important secondary metabolite of Fusarium fungi, exposure to which can cause reproductive disorders through its effects on ovarian granulosa cells (GCs) in many mammals, especially in pigs. This study aimed to investigate the protective effects of Cyanidin-3-O-glucoside (C3G) on [...] Read more.

Zearalenone (ZEN) is an important secondary metabolite of Fusarium fungi, exposure to which can cause reproductive disorders through its effects on ovarian granulosa cells (GCs) in many mammals, especially in pigs. This study aimed to investigate the protective effects of Cyanidin-3-O-glucoside (C3G) on the ZEN-induced negative effects in porcine GCs (pGCs). The pGCs were treated with 30 µM ZEN and/or 20 µM C3G for 24 h; they were divided into a control (Ctrl) group, ZEN group, ZEN+C3G (Z+C) group, and a C3G group. Bioinformatics analysis was used to systematically screen differentially expressed genes (DEGs) in the rescue process. Results showed that C3G could effectively rescue ZEN-induced apoptosis in pGCs, and notably increase cell viability and proliferation. Furthermore, 116 DEGs were identified, and the phosphatidylinositide 3-kinases-protein kinase B (PI3K-AKT) signaling pathway was the center of attention, of which five genes and the PI3K-AKT signaling pathway were confirmed by real-time quantitative PCR (qPCR) and/or Western blot (WB). As analyzed, ZEN inhibited mRNA and protein levels of integrin subunit alpha-7 (ITGA7), and promoted the expression of cell cycle inhibition kinase cyclin-D3 (CCND3) and cyclin-dependent kinase inhibitor 1 (CDKN1A). After the knock-down of ITGA7 by siRNA, the PI3K-AKT signaling pathway was significantly inhibited. Meanwhile, proliferating cell nuclear antigen (PCNA) expression decreased, and apoptosis rates and pro-apoptotic proteins increased. In conclusion, our study demonstrated that C3G exhibited significant protective effects on the ZEN-induced inhibition of proliferation and apoptosis via the ITGA7-PI3K-AKT pathway. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Reproductive and Developmental Toxicology)

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