Prenatal cadmium exposure has inter-generational adverse effects on Sertoli cells through the follicle-stimulating hormone receptor pathway

IN BRIEF: Exposure to cadmium (Cd) during pregnancy can potentially harm the reproductive system of male offspring. This article shows that pregnant woman should be protected from cadmium exposure. ABSTRACT: Exposure to cadmium (Cd) during pregnancy can potentially harm the reproductive system of male offspring, although the full extent of its heritable effects remains partially unresolved. In this study, we examined the inter-generational impacts of Cd using a distinct male-lineage generational model. Pregnant Sprague–Dawley female rats (F0) were administered control or cadmium chloride (0.5, 1 and 2 mg/day) via intra-gastric administration from gestation day 1 to 20. Subsequently, the first filial generation (F1) male rats were mated with untreated females (not exposed to Cd) to produce the second filial generation (F2). Histopathological analysis of the F1 and F2 generations revealed abnormal testicular development, while ultrastructural examination indicated damage to Sertoli cells. Cd exposure also led to alterations in serum hormone levels (gonadotropin-releasing hormone, follicle-stimulating hormone) and reduced follicle-stimulating hormone receptor (FSHR) protein expression in Sertoli cells in the F1 generation. Furthermore, Cd affected the mRNA and protein expression of FSHR pathway factors and DNA methyltransferase, albeit with distinct patterns and inconsistencies observed between the F1 and F2 generations. Overall, our findings indicate that prenatal Cd exposure, using a male-lineage transmission model, can induce inter-generational effects on male reproduction, particularly by causing toxicity in Sertoli cells. This effect appears to be primarily mediated through disruptions in the FSHR pathway and changes in DNA methyltransferase activity in the male testes.