Fetal Growth Retardation and Lack of Hypotaurine in Ezrin Knockout Mice

Nishimura, Tomohiro; Higuchi, Kei; Sai, Yoshimichi; Sugita, Yuki; Yoshida, Yasuhiko; Tomi, Masatoshi; Wada, Masami; Wakayama, Tomohiko; Tamura, Atsushi; Tsukita, Sachiko; Soga, Tomoyoshi; Nakashima, Emi

doi:10.1371/journal.pone.0105423

Cited by 16 publications

(11 citation statements)

References 27 publications

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“…Over the years, different target proteins such as ezrin 61 , IQGAP1 74 , non-muscle myosin IIA 23 or proteins related to the tissue plasminogen activator pathway 75 have been shown to act as S100P binding partners in normal and cancer cells where they are believed to regulate motility and invasion. Interestingly, ezrin knockdown has been shown to play key roles during gestation leading to foetal growth retardation 76 , whilst non-muscle myosin IIA is essential during embryogenesis and placentation 77 and may regulate cellular motility of trophoblasts in culture 78 . However, a role for IQGAP1 and tissue plasminogen activator in trophoblast motility/invasion are yet to be characterised, but both have been shown to be key regulators of cancer motility/invasion 79 – 81 .…”

Section: Discussionmentioning

confidence: 99%

S100P enhances the motility and invasion of human trophoblast cell lines

Tabrizi

Lancaster

Ismail

et al. 2018

Sci Rep

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S100P has been shown to be a marker for carcinogenesis where its expression in solid tumours correlates with metastasis and a poor patient prognosis. This protein’s role in any physiological process is, however, unknown. Here we first show that S100P is expressed both in trophoblasts in vivo as well as in some corresponding cell lines in culture. We demonstrate that S100P is predominantly expressed during the early stage of placental formation with its highest expression levels occurring during the first trimester of gestation, particularly in the invading columns and anchoring villi. Using gain or loss of function studies through overexpression or knockdown of S100P expression respectively, our work shows that S100P stimulates both cell motility and cellular invasion in different trophoblastic and first trimester EVT cell lines. Interestingly, cell invasion was seen to be more dramatically affected than cell migration. Our results suggest that S100P may be acting as an important regulator of trophoblast invasion during placentation. This finding sheds new light on a hitherto uncharacterized molecular mechanism which may, in turn, lead to the identification of novel targets that may explain why significant numbers of confirmed human pregnancies suffer complications through poor placental implantation.

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Section: Discussionmentioning

confidence: 99%

S100P enhances the motility and invasion of human trophoblast cell lines

Tabrizi

Lancaster

Ismail

et al. 2018

Sci Rep

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“…The antioxidant properties of hypotaurine have been repeatedly demonstrated to elicit protective effects against stress-induced cytotoxicity in several contexts ( Fellman and Roth, 1985 ; Aruoma et al, 1988 ; Green et al, 1991 ; Fontana et al, 2004 ; Fontana et al, 2008 ). Hypotaurine was shown to protect against oxidative stress in rat placental trophoblasts, while knockout of the gene coding for ezrin, a membrane-cytoskeletal protein necessary for hypotaurine transport, resulted in depleted fetal plasma hypotaurine and reduced fetal weights of knockout embryos ( Nishimura et al, 2014 ; Nishimura et al, 2015 ). Hypotaurine was also shown to elicit hepatoprotective effects in a rat model of ischemic injury through its antioxidative conversion to taurine ( Sakuragawa et al, 2010 ), and taurine (the downstream product of hypotaurine) was recently shown to reduced hepatic injury in mice after VPA exposure ( Khodayar et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…In humans, L-carnitine has a half-life ranging from 2 to 15 h ( Goa and Brogden, 1987 ), and to our knowledge, there is no data available for mice. Hypotaurine is transported across the plasma membrane in cultured rat syncitiotrophoblast cells, and fetal levels of hypotaurine rely on placental hypotaurine transport ( Nishimura et al, 2014 ; Nishimura et al, 2015 ). Transport of CoA is less studied and poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Embryonic Hypotaurine Levels Contribute to Strain-Dependent Susceptibility in Mouse Models of Valproate-Induced Neural Tube Defects

Steele

Lin

Chen

et al. 2022

Front. Cell Dev. Biol.

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Valproic acid (VPA, valproate, Depakote) is a commonly used anti-seizure medication (ASM) in the treatment of epilepsy and a variety of other neurological disorders. While VPA and other ASMs are efficacious for management of seizures, they also increase the risk for adverse pregnancy outcomes, including neural tube defects (NTDs). Thus, the utility of these drugs during pregnancy and in women of childbearing potential presents a continuing public health challenge. Elucidating the underlying genetic or metabolic risk factors for VPA-affected pregnancies may lead to development of non-teratogenic ASMs, novel prevention strategies, or more targeted methods for managing epileptic pregnancies. To address this challenge, we performed unbiased, whole embryo metabolomic screening of E8.5 mouse embryos from two inbred strains with differential susceptibility to VPA-induced NTDs. We identified metabolites of differential abundance between the two strains, both in response to VPA exposure and in the vehicle controls. Notable enriched pathways included lipid metabolism, carnitine metabolism, and several amino acid pathways, especially cysteine and methionine metabolism. There also was increased abundance of ω-oxidation products of VPA in the more NTD-sensitive strain, suggesting differential metabolism of the drug. Finally, we found significantly reduced levels of hypotaurine in the susceptible strain regardless of VPA status. Based on this information, we hypothesized that maternal supplementation with L-carnitine (400 mg/kg), coenzyme A (200 mg/kg), or hypotaurine (350 mg/kg) would reduce VPA-induced NTDs in the sensitive strain and found that administration of hypotaurine prior to VPA exposure significantly reduced the occurrence of NTDs by close to one-third compared to controls. L-carnitine and coenzyme A reduced resorption rates but did not significantly reduce NTD risk in the sensitive strain. These results suggest that genetic variants or environmental exposures influencing embryonic hypotaurine status may be factors in determining risk for adverse pregnancy outcomes when managing the health care needs of pregnant women exposed to VPA or other ASMs.

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“…Details of the remaining CE–MS‐based metabolomics applications of the past two years can be found in Table .…”

Section: Applicationsmentioning

confidence: 99%

CE–MS for metabolomics: Developments and applications in the period 2014–2016

2016

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CE–MS can be considered a useful analytical technique for the global profiling of (highly) polar and charged metabolites in various samples. Over the past few years, significant advancements have been made in CE–MS approaches for metabolomics studies. In this paper, which is a follow‐up of a previous review paper covering the years 2012–2014 (Electrophoresis 2015, 36, 212–224), recent CE–MS strategies developed for metabolomics covering the literature from July 2014 to June 2016 are outlined. Attention will be paid to new CE–MS approaches for the profiling of anionic metabolites and the potential of SPE coupled to CE–MS is also demonstrated. Representative examples illustrate the applicability of CE–MS in the fields of biomedical, clinical, microbial, plant, and food metabolomics. A complete overview of recent CE–MS‐based metabolomics studies is given in a table, which provides information on sample type and pretreatment, capillary coatings, and MS detection mode. Finally, general conclusions and perspectives are given.

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Fetal Growth Retardation and Lack of Hypotaurine in Ezrin Knockout Mice

Cited by 16 publications

References 27 publications

S100P enhances the motility and invasion of human trophoblast cell lines

S100P enhances the motility and invasion of human trophoblast cell lines

Embryonic Hypotaurine Levels Contribute to Strain-Dependent Susceptibility in Mouse Models of Valproate-Induced Neural Tube Defects

CE–MS for metabolomics: Developments and applications in the period 2014–2016

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