Gestational exposure to paracetamol in rats induces neurofunctional alterations in the progeny

Klein, Rodrigo Moreno; Rigobello, Camila; Vidigal, Camila Borecki; Moura, Kawane F.; Barbosa, Décio Sabbatini; Gerardin, Daniela Cristina Ceccatto; Ceravolo, Graziela Scalianti; Moreira, Estefânia Gastaldello

doi:10.1016/j.ntt.2019.106838

Cited by 20 publications

(20 citation statements)

References 58 publications

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“…The experimental evidence of neurodevelopmental effects. Experimental animal studies have suggested that perinatal APAP exposure, even at low therapeutic doses, increases the risk of brain and behavioural abnormalities in rodents 51,[145][146][147][148][149][150][151] , supporting the epidemiological evidence (Supplementary Table 4). A 2019 study suggested that APAP enters the developing rat brain and cerebrospinal fluid in higher amounts than the adult brain.…”

Section: The Epidemiological Evidence Of Neurodevelopmental Effectssupporting

confidence: 55%

Paracetamol use during pregnancy — a call for precautionary action

Bauer¹,

Swan

Kriebel³

et al. 2021

Nat Rev Endocrinol

106

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Paracetamol (N-acetyl-p-aminophenol (APAP), otherwise known as acetaminophen) is the active ingredient in more than 600 medications used to relieve mild to moderate pain and reduce fever. APAP is widely used by pregnant women as governmental agencies, including the FDA and EMA, have long considered APAP appropriate for use during pregnancy when used as directed. However, increasing experimental and epidemiological research suggests that prenatal exposure to APAP might alter fetal development, which could increase the risks of some neurodevelopmental, reproductive and urogenital disorders. Here we summarize this evidence and call for precautionary action through a focused research effort and by increasing awareness among health professionals and pregnant women. APAP is an important medication and alternatives for treatment of high fever and severe pain are limited. We recommend that pregnant women should be cautioned at the beginning of pregnancy to: forego APAP unless its use is medically indicated; consult with a physician or pharmacist if they are uncertain whether use is indicated and before using on a long-term basis; and minimize exposure by using the lowest effective dose for the shortest possible time. We suggest specific actions to implement these recommendations. This Consensus Statement reflects our concerns and is currently supported by 91 scientists, clinicians and public health professionals from across the globe.

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Section: The Epidemiological Evidence Of Neurodevelopmental Effectssupporting

confidence: 55%

Paracetamol use during pregnancy — a call for precautionary action

Bauer¹,

Swan

Kriebel³

et al. 2021

Nat Rev Endocrinol

106

View full text Add to dashboard Cite

show abstract

“…Two additional papers were excluded after reading the full paper version (in both because paracetamol was not used in these studies, but mentioned in the abstract), and one additional paper was included following citation verification to result in 20 papers (Prisma flowchart, Figure 1). Table I provides an overview on the quality assessment (SYRCLE's risk of bias tool) results [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45]. This reflects a heterogeneous pattern with mainly issues related to blinding (for performance, for detection) procedures in a relevant portion of the studies (unclear or unreported, high risk in 16/20 for both) and allocation concealment (was the method used to conceal the allocation sequence described in sufficient detail to determine whether intervention allocation could have been foreseen before or during enrolment?).…”

Section: Resultsmentioning

confidence: 99%

“…This does not mean that these aspects were not considered during the design or study conduct, but we were not able to extract this information from the methods section description. Table II provides an overview on the characteristics of these studies [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45]. Juvenile species reported are rat (n = 9), zebrafish larvae (n = 6), or mice/mouse (n = 5).…”

Section: Resultsmentioning

confidence: 99%

How to translate neuro-cognitive and behavioural outcome data in animals exposed to paracetamol to the human perinatal setting?

Allegaert

Anker

2020

Arch Med Sci

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IntroductionIntroduction: There are epidemiological – not necessary causal – observations that link perinatal paracetamol (acetaminophen) exposure to impaired neuro-cognition and behaviour, but animal models may assist to better understand the mechanisms.Material and methodsTo provide an overview on preclinical data and mechanisms explored, we conducted a structured literature search on animal models and neuro-cognition and behavioural outcome following perinatal paracetamol exposure.ResultsThis search resulted in 20 papers [rat (n = 9), zebrafish larvae (n = 6), mice (n = 5)], published between 2009 and 2020. Eight discussed pregnancy/fetal paracetamol exposure, 6 juvenile, 6 studies combined pregnancy and juvenile exposure. Quality assessment (SYRCLE’s bias risk) showed a heterogeneous pattern with blinding issues. Most papers (n = 16) described paracetamol exposure without indication, except for an induced fever and repetitive needle pricking (rat), brain injury (mice), and a zebrafish nociception model. Reported outcomes related to biochemistry (mono-amines, amino acids, protein expression), anatomy (teratogen, morphology, nuclear size) or behaviour (spatial memory, motor, social behaviour and exploration, sexual behaviour). On mechanisms, the cumulative data support an interesting ‘cannabinoid’ hypothesis to link paracetamol to neuro-cognitive and behavioural outcome. Besides limited species diversity, there is relevant within-species paracetamol dosing variability (dose, duration) with undocumented exposure.ConclusionsModels should further integrate clinical indications, as non-exposure is the obvious safest setting in the absence of an indication. Besides pain and fever and related to the cannabinoid hypothesis, this should include perinatal brain injury, as there is animal experimental evidence that cannabinoids are neuroprotective in newborn brain injury or asphyxia, further supported by evidence from non-perinatal models of paracetamol-related neuroprotective effects.

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“…Acute APAP intoxication disturbs neurotransmitters including GABA, glutamate, dopamine, serotonin, norepinephrine, and acetylcholine, increases oxidative stress and reactive astrogliosis in the brain, and consequently induces HE (Saad et al, 2018;Vigo et al, 2019). And similar to the case in antibiotics, maternal use of APAP also induces neurofunctional impairments in the progeny (Klein et al, 2020). In addition to the fact that APAP also distributes and is metabolized in the brain which directly affects brain function, the gut-brain axis may play a part therein, and the liver may be an important mediator.…”

Section: Connecting the Dots: Gut-liver-brain Aixs In Drug Toxicitymentioning

confidence: 94%

Connecting the dots: targeting gut microbiota in drug toxicity

Luo¹,

Zhou²

2020

Preprint

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Gut microbiota has been demonstrated to have a vast influence on human health in recent decades and its role in initiating, aggravating, or ameliorating diseases is emerging. Therapeutic strategies have therefore increasingly developed by targeting gut microbial modulation. Recently, its contribution to heterogeneous toxicological responses is also gaining attention, especially in drug-induced toxicity. Oral drugs interact directly with gut microbiota within the gastrointestinal tract and a number of them elicit toxicity mediated by intestinal microbiota. Present studies focus more on the unidirectional influence of how xenobiotics disturb intestinal microbial composition and function and consequently induce altered homeostasis. However, interactions between gut microbiota and xenobiotics are bidirectional and the impact of gut microbiota on xenobiotics especially on drugs should not be neglected. Thus, in this review, we intend to focus on how gut microbiota modulates drug toxicity by highlighting gut microbiota, microbial enzyme, and metabolites to proffer references for seeking common countermeasures in coping with drug toxicity by targeting gut microbiota. Moreover, we give a hypothesis that drugs capable of inducing gut dysbiosis tend to more or less impact the gut-connected organs as evidenced by the drug-induced hepatic encephalopathy, indicating an underlying link among the gut, liver, brain, and other possible organs in drug-induced toxicity.

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Gestational exposure to paracetamol in rats induces neurofunctional alterations in the progeny

Cited by 20 publications

References 58 publications

Paracetamol use during pregnancy — a call for precautionary action

Paracetamol use during pregnancy — a call for precautionary action

How to translate neuro-cognitive and behavioural outcome data in animals exposed to paracetamol to the human perinatal setting?

Connecting the dots: targeting gut microbiota in drug toxicity

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