Effects of Alcohol and Caffeine on Cultured Whole Rat Embryos

Fadel, Raouf; Persaud, T. V. N.

doi:10.1159/000147294

Cited by 17 publications

(5 citation statements)

References 13 publications

(15 reference statements)

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“…(8,37,(39)(40)(41) In the rat, we found that the lateral ventricles more than doubled in size between E14 and E16. (8) Joining of ventricular and subarachnoid fluids After the closure of the neuropores, which in the rat occurs around E11.5, (42,43) the ventricular system remains enclosed until pores are formed in the roof of the fourth ventricle and the fluid in the ventricles becomes continuous with the fluid in the subarachnoid spaces (cranial and spinal, Fig. 3A,B).…”

Section: Ventricular Expansionmentioning

confidence: 99%

The blood–CSF barrier explained: when development is not immaturity

et al. 2008

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It is often suggested that during development the brain barriers are immature. This argument stems from teleological interpretations and experimental observations of the high protein concentrations in fetal cerebrospinal fluid (CSF) and decreases in apparent permeability of passive markers during development. We argue that the developmental blood-CSF barrier restricts the passage of lipid-insoluble molecules by the same mechanism as in the adult (tight junctions) rendering the paracellular pathway an unlikely route of entry. Instead, we suggest that both protein and passive markers are transferred across the epithelium through a transcellular route. We propose that changes in volume of distribution can largely explain the decrease in apparent permeability for passive markers and that developmentally regulated cellular transfer explains changes in CSF protein concentrations. The blood-CSF tight junctions are functionally mature from very early in development, and it appears that transfer from blood into embryonic brain occurs predominately via CSF rather than the vasculature.

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Section: Ventricular Expansionmentioning

confidence: 99%

The blood–CSF barrier explained: when development is not immaturity

et al. 2008

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“…All produce teratogenic effects in rodent embryo cultures, but little progress has been made in identifying the manner in which specific metabolic pathways or developmental processes are affected. Alcohol appears to exert a direct teratogenic effect, but similar effects are also produced by acetaldehyde and the relative importance of these compounds is unclear (Fadel and Persaud 1992;Giavini et al 1992). There is some evidence to suggest that secondary metabolites of phenytoin, generated by oxidation in the fetus or mother, are the important teratogens (Shanks et al 1989;.…”

Section: Defective Maternal Protection From Toxic Metabolitesmentioning

confidence: 99%

Metabolic disorders of embryogenesis

Brown

1994

J of Inher Metab Disea

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Prevention of major physical malformations would represent a significant reduction in the burden of mortality and morbidity in infants and young children. However, preventive and therapeutic approaches must be based on a clear understanding of underlying pathogenic mechanisms. While it is estimated that single gene defects account for up to 10% of cases of major malformation, relatively few of these have been identified and analysed in detail. The recognition of characteristic patterns of developmental anomalies associated with specific enzyme defects has highlighted the important role of the metabolic environment in normal development and offers the possibility of correlating biochemical abnormalities with particular teratogenic effects. Once it is generally appreciated that some forms of structural malformation have a specific biochemical basis, metabolic studies should be performed more often in patients with major developmental anomalies. This should lead to identification of other examples of diseases of this type and the elucidation of molecular mechanisms of human teratogenesis.

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“…Using WEC, Eth, FLUCO and VPA induce severe developmental defects, including abnormalities at the embryonic precursors of facial skeleton (branchial arches): Eth concentrations of 44 mM or higher are teratogenic, while 17 mM is universally accepted as ineffective and therefore used in WEC as solvent for water-insoluble test molecules (Kitchin and Ebron 1984 ; Fadel and Persaud 1992 ; Giavini et al 1992 ; Zhou et al 2011 ); FLUCO is teratogenic at same order of magnitude concentrations (125–500 µM) (Tiboni 1993 ; Menegola et al 2001 ) of the therapeutical plasma level window (13–228 µM) (Santos et al 2010 ); VPA-exposure related to developmental defects at concentrations (31.25–750 µM) (Metruccio et al 2020 ; Battistoni et al 2022 ) consistent with plasma therapeutic levels (347–693 µM or higher) (Turnbull et al 1983 ; Nakashima et al 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Moderate alcohol consumption during pregnancy increases potency of two different drugs (the antifungal fluconazole and the antiepileptic valproate) in inducing craniofacial defects: prediction by the in vitro rat whole embryo culture

et al. 2022

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The prenatal exposure to ethanol (Eth), fluconazole (FLUCO) and sodium valproate (VPA) is related to effects on development, producing characteristic syndromic pictures. Among embryotoxic effects described for the three molecules, the alteration on craniofacial morphogenesis is a common feature in humans and animal models, including rodent embryos developed in vitro. The aim of the present work is to evaluate the developmental effects of low Eth serum concentration (17 mM, corresponding to the legal limit to drive in UK, USA, Canada, and many other countries) in mixture with increasing realistic concentrations of the antifungal drug FLUCO (62.5–500 µM) or with increasing realistic concentrations of the antiepileptic drug VPA (31.25–250 µM). Groups exposed to Eth alone (17–127.5 mM), FLUCO alone (62.5–500 µM) or VPA alone (31.25–750 µM) were also included. The chosen alternative animal model was the post-implantation rat whole embryo culture (WEC). E9.5 embryos were exposed in vitro to the test molecules during the whole test period (48 h, corresponding to the developmental stages characteristics of any vertebrate, for human embryos post-fertilization days 23–31). Data were statistically analyzed and processed for modelling applying the benchmark dose (BMD) and relative potency factor (RPF) approaches. Concentration-related effects on facial outcomes were observed in all experimental groups, with a significant enhancement in the groups co-exposed with Eth in comparison to the single exposures. Data obtained by the present work suggest an additional alert for the assumption of even low levels of alcohol in pregnant women during FLUCO or VPA therapy.

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Effects of Alcohol and Caffeine on Cultured Whole Rat Embryos

Cited by 17 publications

References 13 publications

The blood–CSF barrier explained: when development is not immaturity

The blood–CSF barrier explained: when development is not immaturity

Metabolic disorders of embryogenesis

Moderate alcohol consumption during pregnancy increases potency of two different drugs (the antifungal fluconazole and the antiepileptic valproate) in inducing craniofacial defects: prediction by the in vitro rat whole embryo culture

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