Chronic Mild Stress Protocol Applied to Male Rats, From Peripuberty to Adulthood, Negatively Affects Reproductive Outcomes and Offspring Development

ABSTRACT Background Depression is often observed in reproductive age. After the COVID‐19 pandemic, it became more evident mainly in adolescents. The exposure to stressful situations is strongly related to mental diseases development. In 2009, the Food and Drug Administration (FDA) approved the escitalopram for treatment of depression in children and adolescents. Aims To evaluate the effects of paternal chronic mild stress (CMS), with or without escitalopram treatment, on sperm chromatin protamination, testicular SIRT1 expression, reproductive outcomes, and offspring development using a rat model. Methodology Forty‐four peripubertal male rats were randomly distributed into four groups: sham‐control (SC), escitalopram (E), stress (S), and stress + escitalopram (ES). Animals in the stress and stress+escitalopram groups were subjected to a CMS protocol consisting of nine randomly applied stressors over 8 weeks (postnatal Days 41–97). Escitalopram (10 mg/kg/day) was administered by gavage from postnatal Day 70 for 4 weeks. At adulthood, males were mated with healthy nulliparous females to evaluate reproductive outcomes and offspring development. Testes and epididymides were collected on postnatal Day 114 for the assessment of sperm chromatin protamination and SIRT1 immunoexpression. Results CMS and/or escitalopram treatment reduced sperm chromatin protamination, SIRT1 immunoexpression in the seminiferous epithelium, placental thickness, and increased the frequency of skeletal abnormalities in the offspring. CMS alone also reduced gravid uterus weight, litter weight, fetal weight, total placental weight, implantation, and gestational indices, while increasing preimplantation loss. Conclusions Paternal exposure to CMS from peripuberty to adulthood was associated with impaired reproductive outcomes and offspring development, including skeletal abnormalities, reduced sperm chromatin protamination and decreased testicular SIRT1 immunoexpression. Escitalopram treatment was associated with reduced sperm chromatin protamination, decreased testicular SIRT1 immunoexpression, and an increased frequency of skeletal abnormalities in the offspring.