Paternal kisspeptin-10 treatment ameliorates reproductive and metabolic alterations in the offspring of hypothyroid male rats

Kisspeptin has been proposed as a potential therapy for gonadal and gestational metabolic dysfunctions. However, its role in intergenerational reproductive and metabolic dysfunctions of paternal origin remain unknown. Therefore, this study investigated the effects of paternal hypothyroidism (PH) on the reproductive and metabolic health of F1 offspring and examined whether paternal treatment with kisspeptin-10 (Kp10) could mitigate these adverse effects. F1 offspring were obtained from females mated with males from the Control, Hypo, or Hypo + Kp10 groups. Hypothyroidism in the F0 generation was induced by the administration of propylthiouracil for three months; during the final month, animals in the Hypo + Kp10 group also received Kp10. Pubertal development, genital tract morphometry, hormonal parameters, glycemic homeostasis, and hepatic energy-signaling markers were evaluated in F1 offspring, along with sperm epigenetic regulators in F0 fathers. We found that female F1 offspring of paternal hypothyroid rats exhibited delayed puberty, reduced ovarian weight, elevated ovarian COX-2 expression and progesterone (P4) levels, and decreased expression of genes involved in uterine function ( Pgr , Esr1 , and Lif ) and luteal steroidogenesis ( Star , Hsd3b1 , and Hsd17b5 ). These females also developed insulin resistance, impaired glucose tolerance, and increased hepatic Insr expression. In male F1 offspring, paternal hypothyroidism resulted in increased body weight, reduced testicular weight, elevated expression of Star and Cyp11a1 , decreased Thra1 expression in the testes, and glucose intolerance. Importantly, paternal treatment with kisspeptin-10 (Kp10) largely reversed these adverse effects by restoring body weight, gonadal morphology, testicular gene expression, and glucose tolerance in males while increasing hepatic Mtor expression. In female offspring, paternal Kp10 treatment improved glucose tolerance, reduced body weight, enhanced luteal TRα/ Thra1 expression, and decreased hepatic Insr mRNA expression. Furthermore, PH fathers showed increased sperm expression of Dnmt3a and Suv39h1 , suggesting a possible involvement of sperm epigenetic regulatory pathways, which may contribute to the intergenerational transmission of reproductive and metabolic dysfunction. Overall, our findings suggest that PH programs reproductive and metabolic dysfunction in F1 offspring. Importantly, paternal Kp10 treatment effectively attenuated many of these adverse effects, signifying that kisspeptin may serve as a promising therapeutic strategy to protect offspring health and reduce the intergenerational consequences of paternal hypothyroidism.