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    Effects of paracetamol (acetaminophen) on gene expression and permeability properties of the rat placenta and fetal brain.

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    Author
    Koehn, LM; Huang, Y; Habgood, MD; Kysenius, K; Crouch, PJ; Dziegielewska, KM; Saunders, NR
    Date
    2020
    Source Title
    F1000Research
    Publisher
    F1000 Research Ltd
    University of Melbourne Author/s
    Saunders, Norman; Habgood, Mark; Crouch, Peter; Kysenius, Kai
    Affiliation
    Pharmacology and Therapeutics
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Koehn, L. M., Huang, Y., Habgood, M. D., Kysenius, K., Crouch, P. J., Dziegielewska, K. M. & Saunders, N. R. (2020). Effects of paracetamol (acetaminophen) on gene expression and permeability properties of the rat placenta and fetal brain.. F1000Res, 9, pp.573-. https://doi.org/10.12688/f1000research.24119.2.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/251491
    DOI
    10.12688/f1000research.24119.2
    Open Access at PMC
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477648
    Abstract
    Background: Paracetamol (acetaminophen) is widely used in pregnancy and generally regarded as "safe" by regulatory authorities. Methods: Clinically relevant doses of paracetamol were administered intraperitoneally to pregnant rats twice daily from embryonic day E15 to 19 (chronic) or as a single dose at E19 (acute). Control samples were from un-treated age-matched animals. At E19, rats were anaesthetised, administered a final paracetamol dose, uteruses were opened and fetuses exposed for sample collection. For RNA sequencing, placentas and fetal brains were removed and flash frozen. Fetal and maternal plasma and cerebrospinal fluid were assayed for α-fetoprotein and interleukin 1β (IL1β). Brains were fixed and examined (immunohistochemistry) for plasma protein distribution. Placental permeability to a small molecule ( 14C-sucrose) was tested by injection into either mother or individual fetuses; fetal and maternal blood was sampled at regular intervals to 90 minutes. Results: RNA sequencing revealed a large number of genes up- or down-regulated in placentas from acutely or chronically treated animals compared to controls. Most notable was down-regulation of three acute phase plasma proteins (α-fetoprotein, transferrin, transthyretin) in acute and especially chronic experiments and marked up-regulation of immune-related genes, particularly cytokines, again especially in chronically treated dams. IL1β increased in plasma of most fetuses from treated dams but to variable levels and no IL1β was detectable in plasma of control fetuses or any of the dams. Increased placental permeability appeared to be only from fetus to mother for both 14C-sucrose and α-fetoprotein, but not in the reverse direction. In the fetal brain, gene regulatory changes were less prominent than in the placenta of treated fetuses and did not involve inflammatory-related genes; there was no evidence of increased blood-brain barrier permeability. Conclusion: Results suggest that paracetamol may induce an immune-inflammatory-like response in placenta and more caution should be exercised in use of paracetamol in pregnancy.

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