The blood–brain barrier (BBB) plays a critical role in maintaining central nervous system (CNS) homeostasis. Alterations in BBB permeability have been linked to neurodevelopmental disorders and peripheral nerve dysfunction. While maternal health factors are often emphasized in birth outcomes, paternal preconception health — particularly BBB integrity — remains underexplored in relation to risks such as neonatal facial paralysis. This prospective observational study aims to evaluate surrogate markers of BBB permeability in Indian men prior to conception, assess correlations with reproductive biomarkers (hormonal, inflammatory, and seminal parameters), and investigate potential associations with facial paralysis risk in offspring. The study seeks to elucidate whether paternal systemic endothelial or barrier dysfunction contributes to early neurodevelopmental or cranial nerve outcomes in newborns.

The BBB is a semipermeable endothelial interface that regulates the transport of molecules between the bloodstream and CNS. Disruptions in BBB integrity can result in abnormal neurodevelopment, altered neuronal signaling, and inflammatory processes that may impact peripheral nerve development, including cranial nerves such as the facial nerve (CN VII). Neonatal facial paralysis, though often transient, can result from developmental anomalies or birth-related neuropathology. While maternal and perinatal factors are primary contributors, emerging evidence suggests paternal health — including systemic inflammation, oxidative stress, and endothelial dysfunction — may influence fetal neurodevelopment via epigenetic and biochemical pathways.

1. Assess surrogate markers of BBB integrity in Indian men prior to conception.

2. Evaluate correlations between BBB permeability, semen quality, hormonal levels, and systemic inflammation.

3. Investigate potential associations between preconception paternal BBB integrity and facial paralysis risk in newborns.

Study Design

A prospective cohort study including 200–250 Indian men planning conception, with follow-up of offspring until at least 1 year of age to evaluate cranial nerve outcomes, specifically facial nerve function.

Ethics

Approved by institutional ethics committees; informed consent obtained from all participants.

Inclusion Criteria

Indian males aged 25–45 years. Planning conception within 12 months. No history of CNS or reproductive pathology.

Exclusion Criteria

Pre-existing neurological disorders. Recent infections or chronic inflammatory disease. Exposure to teratogens or medications affecting reproductive or BBB function.

1. Semen Analysis

WHO standards: sperm count, motility, morphology, and DNA fragmentation.

2. Hormonal Profile

Serum testosterone, LH, FSH, and prolactin.

3. Systemic Inflammatory Markers

C-reactive protein (CRP), IL-6, TNF-α.

4. Surrogate BBB Integrity Markers

Peripheral markers of endothelial and barrier function: claudin-5, occludin, matrix metalloproteinases (MMPs).

5. Offspring Assessment

Cranial nerve function examination at birth and at 3, 6, and 12 months. Classification of facial paralysis (unilateral vs. bilateral, transient vs. persistent).

Primary outcome: association between preconception BBB surrogate markers and neonatal facial paralysis. Secondary outcomes: correlations of BBB markers with semen quality, hormonal levels, and inflammatory markers. Multivariate regression adjusting for paternal age, BMI, lifestyle factors, and maternal confounders.

Paternal systemic health, including endothelial and barrier function, may influence early neurodevelopment via epigenetic modifications in sperm and inflammatory signaling. BBB alterations might reflect broader systemic dysfunction, potentially affecting cranial nerve development in offspring.

Potential mechanisms:

Epigenetic modifications in sperm DNA linked to BBB dysfunction may impact fetal neurodevelopment. Systemic inflammation in fathers may indirectly alter the intrauterine environment.

Surrogate peripheral BBB markers may not fully capture CNS barrier dynamics. Facial paralysis at birth has multifactorial etiology; paternal contribution is one of many factors.

Evaluating semipermeable BBB alterations in men prior to conception provides a novel approach to understanding paternal contributions to neonatal neurological outcomes, including facial paralysis. This study could inform preconception counseling and highlight the importance of paternal systemic health in reproductive planning in the Indian population.