Developmental exposure to paracetamol causes biochemical alterations in medulla oblongata

Blecharz-Klin, Kamilla; Joniec-Maciejak, Ilona; Jawna, Katarzyna; Pyrzanowska, Justyna; Piechal, Agnieszka; Wawer, Adriana; Widy-Tyszkiewicz, Ewa

doi:10.1016/j.etap.2015.07.001

Cited by 32 publications

(18 citation statements)

References 53 publications

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“…Developmental exposure to paracetamol has also been shown to modulate adult neurotransmission (e.g. serotonergic, noradrenergic and dopaminergic) in the medulla oblongata and spinal cord in rats (Blecharz‐Klin et al ., ,b), further indicating the neurotoxic potential of paracetamol.…”

Section: Introductionmentioning

confidence: 90%

Adult neurobehavioral alterations in male and female mice following developmental exposure to paracetamol (acetaminophen): characterization of a critical period

et al. 2017

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Paracetamol (acetaminophen) is a widely used non-prescription drug with analgesic and antipyretic properties. Among pregnant women and young children, paracetamol is one of the most frequently used drugs and is considered the first-choice treatment for pain and/or fever. Recent findings in both human and animal studies have shown associations between paracetamol intake during brain development and adverse behavioral outcomes later in life. The present study was undertaken to investigate if the induction of these effects depend on when the exposure occurs during a critical period of brain development and if male and female mice are equally affected. Mice of both sexes were exposed to two doses of paracetamol (30 + 30 mg kg , 4 h apart) on postnatal days (PND) 3, 10 or 19. Spontaneous behavior, when introduced to a new home environment, was observed at the age of 2 months. We show that adverse effects on adult behavior and cognitive function occurred in both male and female mice exposed to paracetamol on PND 3 and 10, but not when exposed on PND 19. These neurodevelopmental time points in mice correspond to the beginning of the third trimester of pregnancy and the time around birth in humans, supporting existing human data. Considering that paracetamol is the first choice treatment for pain and/or fever during pregnancy and early life, these results may be of great importance for future research and, ultimately, for clinical practice. Copyright © 2017 John Wiley & Sons, Ltd.

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Section: Introductionmentioning

confidence: 90%

Adult neurobehavioral alterations in male and female mice following developmental exposure to paracetamol (acetaminophen): characterization of a critical period

et al. 2017

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“…This effect may result from redirecting dopamine conversion to other metabolic pathways. Biochemical analysis of the tissue from the thoracic segment of spinal cord have shown significantly reduced level of dopamine and its metabolites; 3,4‐dihydroxyphenylacetic acid (DOPAC) (at dose 5 mg/kg of paracetamol) and 3‐methoxytyramine (3‐MT) (at dose 15 mg/kg) (Blecharz‐Klin et al, 2015a, 2015b). Disturbances in spinal dopaminergic neurotransmission may adversely affect motor functions.…”

Section: Discussionmentioning

confidence: 99%

“…The concentrations of monoamines (dopamine – DA, 5‐hydroxytryptamine ‐ 5‐HT, noradrenalin ‐ NA), its metabolites (3,4‐dihydroxyphenyl acetic acid – DOPAC, 3‐methoxy‐4‐hydroxyphenylglycol ‐ MHPG, homovanillic acid – HVA, 5‐hydroxyindoleacetic acid ‐ 5‐HIAA) and amino acids (taurine ‐ TAU, histidine ‐ HIS, alanine ‐ ALA, aspartic acid ‐ ASP, glutamic acid ‐ GLU and γ‐aminobutyric acid ‐ GABA) in hypothalamus were estimated by high‐performance liquid chromatography (HPLC) according to the previously described procedure (Blecharz‐Klin et al, 2015a,b). Then tissues were homogenized in ice‐cold 0.1 N perchloric acid and centrifuged at 13,000× g for 15 min at 4 °C.…”

Section: Methodsmentioning

confidence: 99%

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Hypothalamus – Response to early paracetamol exposure in male rats offspring

Blecharz-Klin

Wawer

Pyrzanowska

et al. 2019

Intl J of Devlp Neuroscience

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One of the reasons for using paracetamol during pregnancy is fever. The brain structure responsible for maintaining proper body temperature, but also for controlling some endocrine aspects is hypothalamus. In this study we examined the effect of early pretreatment of paracetamol on hypothalamic neurotransmission in rats' offspring. We used two‐month old rats previously exposed to paracetamol at doses of 5 (P5) and 15 mg/kg (P15) during gestational development and next postnatally. The concentration of monoamines, their metabolites and amino acids in hypothalamus was chromatographically determined. The results of biochemical analysis were compared with the Control animals (Con). We found differences between groups in the concentration of main noradrenaline metabolite in hypothalamus. The control group had significantly higher level of 3‐methoxy‐4‐hydroxyphenylglycol (MHPG) compared with rats exposed to paracetamol (F(2,27) = 7.96, p < 0.005). Simultaneously the level of dopamine (DA) (F(2,27) = 4.33, p < 0.05) and its metabolite ‐ homovanillic acid (HVA) (F(2,27) = 17.03, p < 0.005) was increased in the hypothalamus of animals treated with lower dose of the drug. Biochemical analyses show an increase in 3,4‐dihydroxyphenyl acetic acid (DOPAC) concentration in P5 group compared to the control rats and group treated with higher dose of paracetamol (F(2,27) = 7.37, p < 0.005). In the hypothalamus significant decrease of glutamic acid concentration was also observed in the group treated with paracetamol at dose of 5 mg. These results demonstrated that paracetamol had a significant effect on dopaminergic and noradrenergic neurotransmission and changed the concentration of glutamic acid in hypothalamus ‐ heat‐regulating center and important element of hypothalamic‐pituitary‐ gonadal axis.

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“…Taking into account the problem of dosing, we relied mainly on our earlier experience and data from pharmacokinetic studies in humans (Berlin et al, 1980; Bitzen et al, 1981; Blecharz‐Klin et al, 2013; Blecharz‐Klin et al, 2014; Blecharz‐Klin et al, 2015; Notarianni et al, 1987). Our intention was to demonstrate barely noticeable changes occurring in the central nervous system.…”

Section: Discussionmentioning

confidence: 99%

Effect of prenatal and early life paracetamol exposure on the level of neurotransmitters in rats—Focus on the spinal cord

Blecharz-Klin

Joniec-Maciejak

Jawna

et al. 2015

Intl J of Devlp Neuroscience

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The present study has examined the influence of the prenatal and early life administration of paracetamol on the level of neurotransmitters in the spinal cord of rat pups. The effect of the drug was evaluated in 2-month old Wistar male rats exposed to paracetamol in doses of 5 (P5, n=9) or 15 mg/kg (P15, n=9) p.o. during the prenatal period and after birth until the completion of the second month of life. A parallel control group received tap water (Con, n=9). In this study we have determined the level of monoamines, their metabolites and amino acids in the spinal cord of rats using high performance liquid chromatography (HPLC) in the second month of life. The present experiment demonstrates the action of paracetamol at the molecular level associated with significant modulation of neurotransmission in the spinal cord related to dopaminergic and noradrenergic systems. Simultaneously, paracetamol administration increases the content of an aspartic and glutamic acids in the spinal cord at a critical time during development.

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Developmental exposure to paracetamol causes biochemical alterations in medulla oblongata

Cited by 32 publications

References 53 publications

Adult neurobehavioral alterations in male and female mice following developmental exposure to paracetamol (acetaminophen): characterization of a critical period

Adult neurobehavioral alterations in male and female mice following developmental exposure to paracetamol (acetaminophen): characterization of a critical period

Hypothalamus – Response to early paracetamol exposure in male rats offspring

Effect of prenatal and early life paracetamol exposure on the level of neurotransmitters in rats—Focus on the spinal cord

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