Risk Assessment Using Human Pluripotent Stem Cells: Recent Advances in Developmental Toxicity Screens

Buck, Kristen N.; Nieden, Nicole I. zur

doi:10.1002/9781119283249.ch5

Cited by 3 publications

(3 citation statements)

References 142 publications

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“…Developmental toxicity may be elicited by toxicants due to the cytotoxic nature of the exposure, or because the toxicant alters cell fate trajectories in the absence of cytotoxicity [ 34 ]. Unsurprisingly, therefore, and speaking to the first possibility, all tested tobacco products caused a decline in survival rates that was more severe upon exposure to the three conventional products.…”

Section: Discussionmentioning

confidence: 99%

Embryonic Exposure to Cigarette Smoke Extract Impedes Skeletal Development and Evokes Craniofacial Defects in Zebrafish

Karmach

Madrid

Dasgupta

et al. 2022

IJMS

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Exposure to cigarette smoke represents the largest source of preventable death and disease in the United States. This may be in part due to the nature of the delayed harmful effects as well as the lack of awareness of the scope of harm presented by these products. The presence of “light” versions further clouds the harmful effects of tobacco products. While active smoking in expectant mothers may be reduced by educational and outreach campaigns, exposure to secondhand smoke is often involuntary yet may harm the developing embryo. In this study, we show that the main component of secondhand smoke, sidestream cigarette smoke, from several brands, including harm-reduction versions, triggered unsuccessful hatching at 3 dpf and reduced overall survival at 6 dpf in developing zebrafish. At non-lethal concentrations, craniofacial defects with different severity based on the cigarette smoke extract were noted by 6 dpf. All tested products, including harm-reduction products, significantly impacted cartilage formation and/or bone mineralization in zebrafish embryos, independent of whether the bones/cartilage formed from the mesoderm or neural crest. Together, these results in a model system often used to detect embryonic malformations imply that exposure of a woman to secondhand smoke while pregnant may lead to mineralization issues in the skeleton of her newborn, ultimately adding a direct in utero association to the increased fracture risk observed in children of mothers exposed to cigarette smoke.

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Section: Discussionmentioning

confidence: 99%

Embryonic Exposure to Cigarette Smoke Extract Impedes Skeletal Development and Evokes Craniofacial Defects in Zebrafish

Karmach

Madrid

Dasgupta

et al. 2022

IJMS

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“…Our long-term goal is to develop an effective in vitro platform for teratogenicity screening by establishing a novel culture protocol for the differentiation of human ES cell aggregates. To date, various in vitro assays have been devised in efforts to detect teratogenic exposures, many of which utilize mouse or human ES cells [4,[30][31][32][33]. Inclusion of human ES cells is particularly critical in light of certain chemicals, such as thalidomide, impacting human but not mouse embryogenesis [12].…”

Section: Discussionmentioning

confidence: 99%

Exposure-based assessment of chemical teratogenicity using morphogenetic aggregates of human embryonic stem cells

Marikawa

Chen

Menor

et al. 2020

Reproductive Toxicology

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Pluripotent stem cells recapitulate many aspects of embryogenesis in vitro. Here, we established a novel culture system to differentiate human embryonic stem cell aggregates (HESCA), and evaluated its utility for teratogenicity assessment. Culture of HESCA with modulators of developmental signals induced morphogenetic and molecular changes associated with differentiation of the paraxial mesoderm and neuroectoderm. To examine impact of teratogenic exposures on HESCA differentiation, 18 compounds were tested, for which adequate information on in vivo plasma concentrations is available. HESCA treated with each compound were examined for gross morphology and transcript levels of 15 embryogenesis regulator genes. Significant alterations in the transcript levels were observed for 94% (15/16) of the teratogenic exposures within 5-fold margin, whereas no alteration was observed for 92% (11/12) of the non-teratogenic exposures. Our study demonstrates that transcriptional changes in HESCA serve as predictive indicator of teratogenicity in a manner comparable to in vivo exposure levels.

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“…Comparing MS and SS smoke solutions, our study supported the notion that tobacco has detrimental effects on human osteogenic differentiation with SS smoke, which burns off the tip of the cigarette [ 10 ], being more developmentally osteotoxic than MS smoke, which is the smoke actively inhaled by the smoker. Generally, developmental toxicity may be elicited by toxicants due to the cytotoxic nature of the exposure, because the toxicant alters cell fate trajectories in the absence of cytotoxicity [ 11 ], or by a combination of both. Intriguingly, sidestream smoke solutions from harm-reduction products elicited differentiation defects at sub-toxic concentrations, while developmental effects for conventional tobacco product solutions followed their general cytotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Sidestream Smoke Extracts from Harm-Reduction and Conventional Camel Cigarettes Inhibit Osteogenic Differentiation via Oxidative Stress and Differential Activation of intrinsic Apoptotic Pathways

et al. 2022

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Epidemiological studies suggest cigarette smoking as a probable environmental factor for a variety of congenital anomalies, including low bone mass, increased fracture risk and poor skeletal health. Human and animal in vitro models have confirmed hypomineralization of differentiating cell lines with sidestream smoke being more harmful to developing cells than mainstream smoke. Furthermore, first reports are emerging to suggest a differential impact of conventional versus harm-reduction tobacco products on bone tissue as it develops in the embryo or in vitro. To gather first insight into the molecular mechanism of such differences, we assessed the effect of sidestream smoke solutions from Camel (conventional) and Camel Blue (harm-reduction) cigarettes using a human embryonic stem cell osteogenic differentiation model. Sidestream smoke from the conventional Camel cigarettes concentration-dependently inhibited in vitro calcification triggered by high levels of mitochondrially generated oxidative stress, loss of mitochondrial membrane potential, and reduced ATP production. Camel sidestream smoke also induced DNA damage and caspase9-dependent apoptosis. Camel Blue-exposed cells, in contrast, invoked only intermediate levels of reactive oxygen species insufficient to activate caspase3/7. Despite the absence of apoptotic gene activation, damage to the mitochondrial phenotype was still noted concomitant with activation of an anti-inflammatory gene signature and inhibited mineralization. Collectively, the presented findings in differentiating pluripotent stem cells imply that embryos may exhibit low bone mineral density if exposed to environmental smoke during development.

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Risk Assessment Using Human Pluripotent Stem Cells: Recent Advances in Developmental Toxicity Screens

Cited by 3 publications

References 142 publications

Embryonic Exposure to Cigarette Smoke Extract Impedes Skeletal Development and Evokes Craniofacial Defects in Zebrafish

Embryonic Exposure to Cigarette Smoke Extract Impedes Skeletal Development and Evokes Craniofacial Defects in Zebrafish

Exposure-based assessment of chemical teratogenicity using morphogenetic aggregates of human embryonic stem cells

Sidestream Smoke Extracts from Harm-Reduction and Conventional Camel Cigarettes Inhibit Osteogenic Differentiation via Oxidative Stress and Differential Activation of intrinsic Apoptotic Pathways

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