# Neonatal Clomipramine Exposure Disrupts Epididymal Serotonin Signaling and Programs Sperm Dysfunction in Adult Rats

## TL;DR

Exposure to clomipramine in early life disrupts the epididymal serotonin system in rats, leading to long-term sperm dysfunction in adulthood.

## Contribution

This study is the first to show that neonatal SSRI exposure reprograms epididymal serotonin signaling, causing persistent sperm defects.

## Key findings

- Neonatal CMI exposure alters epididymal 5-HT levels region-specifically, decreasing in caput and increasing in cauda.
- Altered 5-HT homeostasis is linked to reduced sperm concentration, viability, morphology, and motility in adult rats.
- Early-life SSRI exposure increases mitochondrial activity and reactive oxygen species in epididymal sperm.

## Abstract

Studies of adult depressed patients report that selective serotonin (5-HT) reuptake inhibitors (SSRIs) like clomipramine (CMI) have secondary effects on sperm quality. The epididymis possesses an autonomous serotonergic system critical for sperm maturation, whose establishment during neonatal development remains unexplored as a target for SSRI programming. We hypothesized that neonatal CMI exposure would disrupt the developing epididymal 5-HT system, leading to permanent sperm dysfunction. CMI (30 mg/kg s.c.) was administered to male rats between postnatal days 8–21. At 3 months, sperm from the epididymal cauda was evaluated, and 5-HT levels were measured in the testis, caput, and cauda epididymis. Our novel findings demonstrate that neonatal CMI exposure induces region-specific, long-term alterations in epididymal 5-HT levels (decreased in caput, increased in cauda) without affecting testicular 5-HT. This reprogramming of the local serotonergic milieu was associated with reduced sperm concentration, viability, normal morphology, and motility, alongside increased mitochondrial activity and reactive oxygen species. This study reveals, for the first time, that the epididymal serotonergic system is a key target for neonatal SSRI programming, providing a mechanistic link (altered 5-HT homeostasis) between early-life exposure and persistent sperm defects in adulthood.