In utero exposure to therapeutic doses of acetaminophen and ibuprofen accelerates germ cell differentiation in the mouse embryonic testis

NSAIDs and ACE that affect prostaglandin synthesis are widely used by pregnant women. Epidemiological studies have hypothesized a potential relation of testis dysgenesis syndromes such as cryptorchidism and hypospadias to exposure to these molecules during both the first and the second trimesters of gestation. To decipher whether the embryonic gonads themselves are targets for these molecules, we analysed the impact of precocious in utero exposure to NSAIDs and ACE alone or in combination on the early development of the testis during sex determination, using therapeutic doses similar to those administrated in human medications. We found that in utero exposure to ACE, aspirin or ibuprofen affects the germ cell proliferation in embryonic testis. The whole transcriptome of 13.5 dpc (days post coïtum) treated testis suggests different mechanisms of action of these drugs and a functional interaction between both molecules used in combination, in accelerating the germ cell differentiation. We identified that ACE and ibuprofen exposure through the up-regulation of Dnmt3L expression induces advanced epigenetic reprograming of the germline and enhanced glycogen storage within the testis cords through the activation of extracellular matrix genes expression. In addition, we identified for the first time the prostaglandin production pattern in the embryonic gonad and showed that PGD2, PGE2 and PGI2 were the targets of ACE and NSAIDs drugs. These features might affect the formation and maturation of postnatal testis and secondary reproductive organs leading to male infertility in adult age. Overall design: examination of the impact of in utero exposure to NSAIDs and ACE on testis organogenesis

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Rossitto M, Marchive C, Pruvost A, Sellem E, Ghettas A, Badiou S, Sutra T, Poulat F, Philibert P, Boizet-Bonhoure B