Developmental Toxicity: Extrapolation Across Species

Hoar, Richard M.

doi:10.3109/10915819509008677

Cited by 11 publications

(5 citation statements)

References 19 publications

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“…This is crucial for detoxification of cells, especially oxidative stress conditions and regular embryonic development [21] . Although these studies described the required toxic dose and perturbations of organ development, these results cannot necessarily be extrapolated to other species or humans due to the known species-specificity of thalidomide [22] . Therefore, a consistent and predictive developmental toxicity model based on hESCs requires an in-depth insight into the molecular mechanisms that explain the adverse developmental potential of a drug in the concentration range applied under in vivo conditions.…”

Section: Introductionmentioning

confidence: 99%

Identification of Thalidomide-Specific Transcriptomics and Proteomics Signatures during Differentiation of Human Embryonic Stem Cells

Meganathan¹,

Jagtap²,

Wagh³

et al. 2012

PLoS ONE

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Embryonic development can be partially recapitulated in vitro by differentiating human embryonic stem cells (hESCs). Thalidomide is a developmental toxicant in vivo and acts in a species-dependent manner. Besides its therapeutic value, thalidomide also serves as a prototypical model to study teratogenecity. Although many in vivo and in vitro platforms have demonstrated its toxicity, only a few test systems accurately reflect human physiology. We used global gene expression and proteomics profiling (two dimensional electrophoresis (2DE) coupled with Tandem Mass spectrometry) to demonstrate hESC differentiation and thalidomide embryotoxicity/teratogenecity with clinically relevant dose(s). Proteome analysis showed loss of POU5F1 regulatory proteins PKM2 and RBM14 and an over expression of proteins involved in neuronal development (such as PAK2, PAFAH1B2 and PAFAH1B3) after 14 days of differentiation. The genomic and proteomic expression pattern demonstrated differential expression of limb, heart and embryonic development related transcription factors and biological processes. Moreover, this study uncovered novel possible mechanisms, such as the inhibition of RANBP1, that participate in the nucleocytoplasmic trafficking of proteins and inhibition of glutathione transferases (GSTA1, GSTA2), that protect the cell from secondary oxidative stress. As a proof of principle, we demonstrated that a combination of transcriptomics and proteomics, along with consistent differentiation of hESCs, enabled the detection of canonical and novel teratogenic intracellular mechanisms of thalidomide.

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Section: Introductionmentioning

confidence: 99%

Identification of Thalidomide-Specific Transcriptomics and Proteomics Signatures during Differentiation of Human Embryonic Stem Cells

Meganathan¹,

Jagtap²,

Wagh³

et al. 2012

PLoS ONE

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“…The clinical trials of various medicines and antiviral medications, however, rarely include pregnant women in their cohorts due to ethical considerations, as has been noted for vaccine safety studies [ 308 ]. Therefore, even though the danger in animals is not always a reliable indicator of the same risk in people [ 309 ], animal studies are occasionally the only source to evaluate how experimental medical interventions would harm the fetus [ 310 ]. Because there are not any clinical trials conducted while pregnant, the safety of a medicine for pregnant women can only be determined after it is sold and used.…”

Section: Vaccines and Antiviral Therapy In Pregnancymentioning

confidence: 99%

Gestational Viral Infections: Role of Host Immune System

Beltrami,

Rizzo,

Schiuma

et al. 2023

Microorganisms

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Viral infections in pregnancy are major causes of maternal and fetal morbidity and mortality. Infections can develop in the neonate transplacentally, perinatally, or postnatally (from breast milk or other sources) and lead to different clinical manifestations, depending on the viral agent and the gestational age at exposure. Viewing the peculiar tolerogenic status which characterizes pregnancy, viruses could exploit this peculiar immunological status to spread or affect the maternal immune system, adopting several evasion strategies. In fact, both DNA and RNA virus might have a deep impact on both innate and acquired immune systems. For this reason, investigating the interaction with these pathogens and the host’s immune system during pregnancy is crucial not only for the development of most effective therapies and diagnosis but mostly for prevention. In this review, we will analyze some of the most important DNA and RNA viruses related to gestational infections.

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“…Unfortunately, in recent history, the initial COVID-19 vaccine trials also excluded pregnant women, preventing women to benefit from the advantages of vaccination [ 8 , 9 ]. In the absence of data from human studies, one can only rely on pre-clinical and/or animal data, although there are limitations with respect to the extrapolation of animal data to humans [ 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Experiences and Perspectives of Marketing Authorisation Holders towards Medication Safety Monitoring during Pregnancy: A Pan-European Qualitative Analysis

Sillis

Foulon

Verbakel

et al. 2022

IJERPH

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Although marketing authorisation holders (MAHs) are involved in monitoring medication safety, it was unclear how they experience their role and current monitoring activities in pregnancy. Therefore, a qualitative study using online focus groups with MAHs and the Belgian umbrella organisation of MAHs was conducted in June–July 2021. In total, 38 representatives of nine organisations participated. Overall, participants reported multiple difficulties with data collection, including underreporting, collection of incomplete information, and loss to follow-up. The limited number of high-quality data collected, the unknown denominator and the lack of comparator data complicate MAHs’ data processing activities, preventing them to timely provide evidence in the pregnancy label. Three ‘conflicts’ inherent to the specific position of MAHs were identified explaining the difficulties they experience, i.e., (1) mistrust from patients and healthcare professionals (HCPs); (2) MAHs’ legal obligations and regulatory framework; (3) MAHs’ position outside the healthcare context. To overcome these barriers, MAHs suggested that data registration should occur in close collaboration with patients and HCPs, organised within the healthcare context and performed by using a user-friendly system. In conclusion, the reported difficulties and underlying conflicts of MAHs highlight the need for more effective, collaborative data collection strategies to generate new evidence on this topic.

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Developmental Toxicity: Extrapolation Across Species

Cited by 11 publications

References 19 publications

Identification of Thalidomide-Specific Transcriptomics and Proteomics Signatures during Differentiation of Human Embryonic Stem Cells

Identification of Thalidomide-Specific Transcriptomics and Proteomics Signatures during Differentiation of Human Embryonic Stem Cells

Gestational Viral Infections: Role of Host Immune System

Experiences and Perspectives of Marketing Authorisation Holders towards Medication Safety Monitoring during Pregnancy: A Pan-European Qualitative Analysis

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