Gestational exposure to PNMC reduces offspring gamete numbers by disrupting oocyte meiosis and spermatogenesis

3-Methyl-4-nitrophenol (PNMC) is a prevalent nitrophenolic endocrine disruptor found in pregnant women, with known effects on offspring growth and development. However, its impact on offspring fertility remains unexplored. This study investigates the effects of PNMC exposure during pregnancy on offspring fertility and the underlying mechanisms. Our fertility assessments revealed that PNMC exposure during pregnancy reduced the number of follicles and spermatozoa in offspring, though it did not affect their quality. In male offspring, PNMC exposure impaired spermatogenesis by reducing the number of Sertoli cells and spermatogonia. In female offspring, exposure disrupted the first meiotic prophase (MPI) of oocytes, leading to a reduced number of diplotene oocytes available for primordial follicle assembly. This depletion of primordial follicle reserve ultimately resulted in subfertility. Specifically, PNMC exposure hindered homologous recombination-mediated DNA double-strand break repair, triggering activation of the meiotic checkpoint and leading to MPI arrest. This arrested progression resulted in a depletion of diplotene oocytes. This is the first study to provide comprehensive evidence on the effects of PNMC exposure during pregnancy on offspring reproductive capacity, elucidating key pathways. These findings emphasize the need for stricter regulatory measures to limit PNMC exposure and offer new insights into the etiology of idiopathic oligozoospermia and diminished ovarian reserve.