Ibuprofen Is Deleterious for the Development of First-Trimester Human Fetal Ovary Ex Vivo

Abstract

Does ibuprofen use during the first trimester of pregnancy interfere with the development of the human fetal ovary? SUMMARY ANSWER: In human fetuses, ibuprofen exposure is deleterious for ovarian germ cells. WHAT IS KNOWN ALREADY: In utero stages of ovarian development define the future reproductive capacity of a woman. In rodents, analgesics can impair the development of the fetal ovary leading to early onset of fertility failure. Ibuprofen, which is available over-thecounter, has been reported as a frequently consumed medication during pregnancy, especially during the first trimester when the ovarian germ cells undergo crucial steps of proliferation and differentiation. STUDY DESIGN, SIZE, DURATION: Organotypic cultures of human ovaries obtained from 7 to 12 developmental week (DW) fetuses were exposed to ibuprofen at 1-100 μM for 2, 4 or 7 days. For each individual, a control culture (vehicle) was included and compared to its treated counterpart. A total of 185 individual samples were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Ovarian explants were analyzed by flow cytometry, immunohistochemistry and quantitative PCR. Endpoints focused on ovarian cell number, cell death, proliferation and germ cell complement. To analyze the possible range of exposure, ibuprofen was measured in the umbilical cord blood from the women exposed or not to ibuprofen prior to termination of pregnancy. MAIN RESULTS AND THE ROLE OF CHANCE: Human ovarian explants exposed to 10 and 100 μM ibuprofen showed reduced cell number, less proliferating cells, increased apoptosis and a dramatic loss of germ cell number, regardless of the gestational age of the fetus. Significant effects were observed after 7 days of exposure to 10 μM ibuprofen. At this concentration, apoptosis was observed as early as 2 days of treatment, along with a decrease in M2A-positive germ cell number. These deleterious effects of ibuprofen were not fully rescued after 5 days of drug withdrawal. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: This study was performed in an experimental setting of human ovaries explants exposed to the drug in culture, which may not fully recapitulate the complexity of in vivo exposure and organ development. Inter-individual variability is also to be taken into account. WIDER IMPLICATIONS OF THE FINDINGS: Whereas ibuprofen is currently only contra-indicated after 24 weeks of pregnancy, our results points to a deleterious effect of this drug on first trimester fetal ovaries ex vivo. These findings deserve to be considered in light of the

Exposure of human fetal kidneys to mild analgesics interferes with early nephrogenesis

“…The Ibu‐induced glomerular density decrease was associated with a low density of PCNA‐positive proliferating cells in the nephrogenic zone, where the classic differentiating areas had disappeared, but a steady percentage of EdU proliferating cells on the whole explant. Consistent with previous experimental data in human embryonic kidney (HEK) 293 cells, 69 ibuprofen‐triggered apoptosis in human fetal kidney explants, a phenomenon also reported in human fetal ovarian explants 60 . In newborn rats exposed to ibuprofen, an altered proliferation/apoptosis ratio associated with decreased nephrons counts was also described 15 .…”

“…Explants were submitted to a sequential enzymatic digestion procedure adapted from Leverrier‐Penna et al 60 in order to obtain single cell suspensions. Briefly, kidney pieces were first digested in 0.25% Trypsin‐0.02% EDTA (#T4049, Sigma‐Aldrich) for 5 minutes at 37°C.…”

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

“…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).…”

Remoção e degradação de fármacos e produtos de higiene em esgoto sanitário em reatores anaeróbios: estratégias de uso de cossubstratos e caracterização taxonômica dos microrganismos

“…Consequentemente, organismos aquáticos e terrestres podem sofrer efeitos adversos em decorrência da exposição contínua a esses compostos biologicamente ativos (GONZALEZ-REY et al, 2012;VELDHOEN et al 2014;LEVERRIER-PENNA et al 2018;PRUD'HOMME et al 2018). Isso porque, a estrutura química de muitos fármacos e produtos de higiene são semelhantes a compostos de sinalização natural e aleloquímicos, podendo resultar em expressão gênica, bloqueio de receptores da membrana celular ou interrupção do sinal de transdução (GARCÍA-CAMBERO et al, 2015).…”

“…Isso porque, a estrutura química de muitos fármacos e produtos de higiene são semelhantes a compostos de sinalização natural e aleloquímicos, podendo resultar em expressão gênica, bloqueio de receptores da membrana celular ou interrupção do sinal de transdução (GARCÍA-CAMBERO et al, 2015). IBU, por exemplo, pode ser prejudicial à proliferação celular em células embrionárias humanas (LEVERRIER-PENNA et al 2018). O TCS, pode resultar em desenvolvimento de genes de resistência em bactérias patogênicas e, inclusive, em resistência cruzada a antibióticos (MCNAMARA, LAPARA, e NOVAK 2014;CAREY et al 2016).…”