The Analgesic Dipyrone Affects Pregnancy Outcomes and Endocrine-Sensitive Endpoints in Female and Male Offspring Rats

Abstract Dipyrone is an analgesic and antipyretic drug commonly used in many countries. Although generally not recommended during pregnancy, it is known that many women use dipyrone during the gestational period. In this study, we investigated the endocrine and reproductive effects of dipyrone in fe...

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Published in:Toxicological sciences 2022-04, Vol.187 (1), p.80-92
Main Authors: Passoni, Marcella Tapias, Krebs Ribeiro, Daniele Cristine, França de Almeida, Samara Christina, Furtado da Costa, Bruna, Grechi, Nicole, Lima Tolouei, Sara Emilia, Curi, Tatiana Zauer, Degraf Cavallin, Mônica, Romano, Renata Marino, Romano, Marco Aurélio, Spercoski, Katherinne Maria, Carvalho dos Santos, Ariany, Carvalho Souza, Roosevelt Isaias, Dalsenter, Paulo Roberto, Martino-Andrade, Anderson Joel
Format: Article
Language:English
Subjects:
Adult
Analgesics - toxicity
Animals
Dipyrone - toxicity
Dose-Response Relationship, Drug
Endocrine Disruptors - toxicity
Female
Genitalia
Humans
Male
Pregnancy
Pregnancy Outcome
Prenatal Exposure Delayed Effects - chemically induced
Rats
Reproduction
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Summary:Abstract Dipyrone is an analgesic and antipyretic drug commonly used in many countries. Although generally not recommended during pregnancy, it is known that many women use dipyrone during the gestational period. In this study, we investigated the endocrine and reproductive effects of dipyrone in female and male offspring rats exposed in utero from gestational days 10–21. Pregnant rats were treated with dipyrone at 25, 75, and 225 mg/kg/day via oral gavage. Developmental landmarks—anogenital index (AGI), number of nipples, vaginal opening, first estrus, and preputial separation—were evaluated in the offspring. Reproductive parameters, including estrous cycle regularity, daily sperm production, weight and histopathology of reproductive organs, steroid hormone levels, and gene expression of selected markers of reproductive function were assessed at adulthood. At the highest dose, dipyrone induced a significant increase in postimplantation losses/fetal death and delayed parturition in dams. Offspring exposed in utero to the highest dose also exhibited significant changes in some early life markers of endocrine disruption, in particular increased AGI in females, indicating a proandrogenic effect, and increased rate of retained nipples in males, indicating an antiandrogenic response. No changes were observed in markers of puberty onset or reproductive parameters at adulthood. These results suggest that exposure to therapeutically relevant doses of dipyrone may induce mild endocrine disruptive effects that can be detected in late pregnancy and early life. Such effects may be relevant considering dipyrone use by pregnant women and the possibility of coexposures with other endocrine disruptors.
ISSN:1096-6080
1096-0929
DOI:10.1093/toxsci/kfac016