Transcriptomic analysis of 30dpp ovaries and 35dpp testes exposed to the cocktails of pharmaceuticals ibuprofen (IBU), 2hydroxyIBU (2hIBU), diclofenac (DCF) and 17a ethinyl-estradiol (EE2) in mice

The endocrine disrupting pharmaceuticals, non-steroidal anti-inflammatory drugs (NSAIDs) and 17α-ethinyl-estradiol (EE2), are among the most relevant molecules found in aquatic ecosystems, surface and drinking water due to their incomplete removal by wastewater treatment plants. Exposure to therapeutic doses has a negative impact on gonadal development and fertility in rodent models; however, the effects of their chronic exposure at lower doses are not known. In this study, we investigated the impact of chronic exposure to a mixture containing ibuprofen, 2hydroxy-ibuprofen, diclofenac, and EE2 at two environmentally relevant doses (added to the drinking water from fetal life, 8.5 dpc, until puberty) on the reproductive tract in F1 exposed mice and their F2 offspring. In F1 animals, exposure delayed male puberty and accelerated female puberty. In post-pubertal F1 testes and ovaries, differentiation/maturation of the different gonad cell types was altered, and some of these modifications were observed also in the non-exposed F2 generation. Transcriptomic analysis of post-pubertal testes and ovaries of F1 (exposed) and F2 animals revealed significant changes in gene expression profiles and enriched pathways, particularly the inflammasome, metabolism and extracellular matrix pathways, compared with controls (non-exposed). This suggested that exposure to these drug cocktails has an inter-generational impact (Int. J. Mol. Sci. 2023, 24, 5890. /doi: 10.3390/ijms24065890)