Analgesic exposure in pregnant rats affects fetal germ cell development with inter-generational reproductive consequences

Dean, Afshan; Driesche, Sander van den; Wang, Yili; McKinnell, Chris; MacPherson, Sarah E.; Eddie, Sharon L.; Kinnell, Hazel L.; Hurtado-Gonzalez, Pablo; Chambers, Thomas K.; Stevenson, Kerrie; Wolfinger, Elke; Hrabálková, Lenka; Calarrão, Ana; Bayne, Rosemary A. L.; Hagen, Casper P; Mitchell, Rod T; Anderson, Richard A.; Sharpe, Richard M.

doi:10.1038/srep19789

Cited by 63 publications

(98 citation statements)

References 59 publications

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“…Conversely, adult mouse sperm parameters are not affected after in utero exposure to low doses of ASA or IBU (25). Similarly, in vivo administration of APAP or indomethacin to pregnant rats during embryogenesis decreases the number of fetal germ cells and accelerates their embryonic differentiation but does not affect the fertility of adult male rats (26). In females, the number of primordial germ cells is reduced (27) and meiotic entry delayed (26) in fetal mouse and rat ovaries, respectively, leading to a decreased number of follicles in adult mouse ovaries (27) and reduced fertility in F1 and F2 rat females (26).…”

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confidence: 99%

“…Similarly, in vivo administration of APAP or indomethacin to pregnant rats during embryogenesis decreases the number of fetal germ cells and accelerates their embryonic differentiation but does not affect the fertility of adult male rats (26). In females, the number of primordial germ cells is reduced (27) and meiotic entry delayed (26) in fetal mouse and rat ovaries, respectively, leading to a decreased number of follicles in adult mouse ovaries (27) and reduced fertility in F1 and F2 rat females (26). In addition, exposure of ex vivo cultures of human embryonic ovaries to IBU induces a decrease in the germ-cell pool due to a decrease in their proliferation and an increase in their apoptosis (28).…”

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confidence: 99%

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Intergenerational effects on mouse sperm quality after in utero exposure to acetaminophen and ibuprofen

et al. 2018

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Nonsteroidal antiinflammatory drugs and analgesic drugs, such as N-acetyl- p-aminophenol (APAP; acetaminophen, paracetamol), are widely used by pregnant women. Accumulating evidence has indicated that these molecules can favor genital malformations in newborn boys and reproductive disorders in adults. However, the consequences on postnatal testis development and adult reproductive health after exposure during early embryogenesis are still unknown. Using the mouse model, we show that in utero exposure to therapeutic doses of the widely used APAP-ibuprofen combination during the sex determination period leads to early differentiation and decreased proliferation of male embryonic germ cells, and early 5-methylcytosine and extracellular matrix protein deposition in 13.5 d postcoitum exposed testes. Consequently, in postnatal testes, Sertoli-cell maturation is delayed, the Leydig-cell compartment is hyperplasic, and the spermatogonia A pool is decreased. This results in a reduced production of testosterone and in epididymal sperm parameter defects. We observed a reduced sperm count (19%) in utero-exposed (F0) adult males and also a reduced sperm motility (40%) in their offspring (F1) when both parents were exposed, which leads to subfertility among the 6 mo old F1 animals. Our study suggests that the use of these drugs during the critical period of sex determination affects the germ-line development and leads to adverse effects that could be passed to the offspring.-Rossitto, M., Marchive, C., Pruvost, A., Sellem, E., Ghettas, A., Badiou, S., Sutra, T., Poulat, F., Philibert, P., Boizet-Bonhoure, B. Intergenerational effects on mouse sperm quality after in utero exposure to acetaminophen and ibuprofen.

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confidence: 99%

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confidence: 99%

Intergenerational effects on mouse sperm quality after in utero exposure to acetaminophen and ibuprofen

et al. 2018

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“…In F1 females, there was a delay in meiotic entry in oogonia. Following in-utero paracetamol exposure, adult female offspring had reduced ovary size and exhibited reduced litter size in adulthood, while no reproductive effects were seen in adult males, suggesting a potential compensatory mechanism between fetal life and adulthood 85. In another study, exposure of pregnant rats to a much lower dose of paracetamol (50 mg/kg/day) from 7 days postconception to birth resulted in a reduction in follicle number in female offspring at 2 months postnatally and also a reduction in pups per litter at 6 months of age 86…”

Section: Effects Of Exposure To Paracetamol On Male Reproductive Healthmentioning

confidence: 95%

“…To investigate this, in-vivo studies of in-utero paracetamol exposure have been conducted in rodents 85 86. In one study, pregnant rats were exposed to paracetamol (350 mg/kg/day) from e15.5 to e18.5, which resulted in altered germ cell development in both sexes of offspring 85. In males, there was an accelerated loss of expression of a pluripotency marker (OCT4), suggesting germ cell differentiation from gonocyte to spermatogonia had occurred prematurely.…”

Section: Effects Of Exposure To Paracetamol On Male Reproductive Healthmentioning

confidence: 99%

Assessing the impact of in-utero exposures: potential effects of paracetamol on male reproductive development

Kilcoyne

Mitchell

2017

Arch Dis Child

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Human male reproductive disorders (cryptorchidism, hypospadias, testicular cancer and low sperm counts) are common and some may be increasing in incidence worldwide. These associated disorders can arise from subnormal testosterone production during fetal life. This has resulted in a focus on in-utero environmental influences that may result in reproductive effects on the offspring in later life. Over recent years, there has been a dramatic increase in the scientific literature describing associations between in-utero environmental exposures (eg, industrial chemicals and pharmaceuticals) and subsequent reproductive outcomes in male offspring. This includes studies investigating a potential role for in-utero analgesic exposure(s) on the fetal testis; however, providing definitive evidence of such effects presents numerous challenges. In this review, we describe an approach to assessing the potential clinical relevance of in-utero (and postnatal) environmental exposures on subsequent male reproductive function using exposure to the analgesic paracetamol as an example.

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“…This effect is a result of inhibition of prostaglandin biosynthesis playing role in the testosterone synthesis in fetal testes (Gupta and Goldaman, 1986; Gupta, 1989). Nevertheless it seems, that paracetamol and other mild analgesics, regardless of gender, causes a decline in reproductive health (Dean et al, 2016; Holm et al, 2016). Recent data reported that in rodents the exposure to paracetamol or its precursor – aniline during pregnancy impairs also female reproductive development and fertility.…”

Section: Introductionmentioning

confidence: 99%

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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Analgesic exposure in pregnant rats affects fetal germ cell development with inter-generational reproductive consequences

Cited by 63 publications

References 59 publications

Intergenerational effects on mouse sperm quality after in utero exposure to acetaminophen and ibuprofen

Intergenerational effects on mouse sperm quality after in utero exposure to acetaminophen and ibuprofen

Assessing the impact of in-utero exposures: potential effects of paracetamol on male reproductive development

Hypothalamus – Response to early paracetamol exposure in male rats offspring

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