Perinatal paracetamol exposure in mice does not affect the development of allergic airways disease in early life

Lee, Debbie C P; Walker, Simone A.; Byrne, Adam; Gregory, Lisa G.; Buckley, James; Bush, Andrew; Shaheen, Seif O.; Saglani, Sejal; Lloyd, Clare M.

doi:10.1136/thoraxjnl-2014-205280

Cited by 14 publications

(8 citation statements)

References 33 publications

(48 reference statements)

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“…Unexpectedly, APAP caused a marked attenuation of the HDM response. A recently published report has shown that, in mice, maternal exposure to APAP during pregnancy and lactation did not enhance HDM-induced allergic airway disease in offspring (Lee et al, 2015). Our study is also consistent with a lack of causality between APAP and asthma as proposed by Heintze and Petersen (2013).…”

Section: Discussionsupporting

confidence: 81%

Acetaminophen Attenuates House Dust Mite–Induced Allergic Airway Disease in Mice

Smith

Thrall

Cloutier

et al. 2016

The Journal of Pharmacology and Experimental Therapeutics

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Epidemiologic evidence suggests that N-acetyl-para-aminophenol (APAP) may play a role in the pathogenesis of asthma, likely through pro-oxidant mechanisms. However, no studies have investigated the direct effects of APAP on the development of allergic inflammation. To determine the likelihood of a causal relationship between APAP and asthma pathogenesis, we explored the effects of APAP on inflammatory responses in a murine house dust mite (HDM) model of allergic airway disease. We hypothesized that APAP would enhance the development of HDM-induced allergic inflammation. The HDM model consisted of once daily intranasal instillations for up to 2 weeks with APAP or vehicle administration 1 hour prior to HDM during either week 1 or 2. Primary assessment of inflammation included bronchoalveolar lavage (BAL), cytokine expression in lung tissue, and histopathology. Contrary to our hypothesis, the effects of HDM treatment were substantially diminished in APAP-treated groups compared with controls. APAP-treated groups had markedly reduced airway inflammation: including decreased inflammatory cells in the BAL fluid, lower cytokine expression in lung tissue, and less perivascular and peribronchiolar immune cell infiltration. The anti-inflammatory effect of APAP was not abrogated by an inhibitor of cytochrome P450 (P450) metabolism, suggesting that the effect was due to the parent compound or a non-P450 generated metabolite. Taken together, our studies do not support the biologic plausibility of the APAP hypothesis that APAP use may contribute to the causation of asthma. Importantly, we suggest the mechanism by which APAP modulates airway inflammation may provide novel therapeutic targets for asthma.

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Section: Discussionsupporting

confidence: 81%

Acetaminophen Attenuates House Dust Mite–Induced Allergic Airway Disease in Mice

Smith

Thrall

Cloutier

et al. 2016

The Journal of Pharmacology and Experimental Therapeutics

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“…After paracetamol was administered to pregnant mice, the adult offspring demonstrated airway inflammation and severe neurodevelopmental aberrations (25,26). Meanwhile, other studies have found the opposite, concluding that paracetamol use during pregnancy does not cause increased neurodevelopmental symptoms or allergic airway diseases in the offspring (27,28). The present study found no differences in the participants' neurodevelopment, nor any symptoms that would indicate the development of autism spectrum diseases or asthma, although it is known that autism spectrum disorders are seldom diagnosed before the age of three years (Tables 2 and 3).…”

Section: Discussionmentioning

confidence: 99%

Follow‐up study of the early, randomised paracetamol trial to preterm infants, found no adverse reactions at the two‐years corrected age

et al. 2018

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Aim We examined the long‐term outcomes and safety of early intravenous paracetamol for ductus arteriosus closure at a corrected age of two years. Methods This was a follow‐up of the 2013–2014 randomised, double‐blind Preterm Infant's Paracetamol Study at Oulu University Hospital, Finland, which recruited 48 very preterm infants within 24 hours of birth. They received intravenous paracetamol or a placebo for four days. In 2015–2017, we followed up 44 infants (92%) at two years of corrected age. This included clinical and neurodevelopmental assessments and a parental medical history questionnaire. Results The 44 infants (55% boys) were born at 235–316 weeks of gestation. No differences in the cardiac parameters, including blood pressures and ultrasound scan results, were found. Neurodevelopmental stages, as quantified by the Griffiths test, were similar. No signs of autism were reported. Asthma medication was more common in the control group, but the difference was not significant. Atopy scores, numbers of infections and the use of public health services were similar between the two groups. Conclusion No long‐term adverse reactions of early intravenous paracetamol were detected two years later. Larger trials are needed on the safety and efficacy of paracetamol prophylaxis for early ductal closure in very preterm infants.

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“…However, whether the association of maternal paracetamol intake and childhood asthma represents a causal relationship remains to be firmly established. A recent study of perinatal exposure to paracetamol in mice failed to provide evidence to support a causal relationship . Other medicines besides paracetamol have been shown to influence allergic disease.…”

Section: In Utero Exposures That Influence Allergymentioning

confidence: 99%

Does allergy begin in utero?

Lockett

Huoman

Holloway

2015

Pediatric Allergy Immunology

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It has been recognized for centuries that allergic disease runs in families, implying a role for genetic factors in determining individual susceptibility. More recently, a range of evidence shows that many of these genetic factors, together with in utero environmental exposures, lead to the development of allergic disease through altered immune and organ development. Environmental exposures during pregnancy including diet, nutrient intake and toxin exposures can alter the epigenome and interact with inherited genetic and epigenetic risk factors to directly and indirectly influence organ development and immune programming. Understanding of these factors will be essential in identifying at-risk individuals and possible development of therapeutic interventions for the primary prevention of allergic disease. In this review, we summarize the evidence that suggests allergic disease begins in utero, together with possible mechanisms for the effect of environmental exposures during pregnancy on allergic disease risk, including epigenetics.

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Perinatal paracetamol exposure in mice does not affect the development of allergic airways disease in early life

Cited by 14 publications

References 33 publications

Acetaminophen Attenuates House Dust Mite–Induced Allergic Airway Disease in Mice

Acetaminophen Attenuates House Dust Mite–Induced Allergic Airway Disease in Mice

Follow‐up study of the early, randomised paracetamol trial to preterm infants, found no adverse reactions at the two‐years corrected age

Does allergy begin in utero?

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