The dual nature of micronutrients on fertility: too much of a good thing?

Objective: To study the effects of generally considered safe doses of antioxidant micronutrient supplementation on semen parameters, systemic redox balance, sperm DNA structural integrity, and fertility.

Design: Given ethical limitations in human studies, this dose escalation study examined the effects of common water-soluble antioxidant micronutrients (vitamin C, zinc, folate, and carnitine) on semen parameters, redox status, DNA integrity, and fertility outcomes in healthy male mice over one spermatogenic cycle. The study was partially repeated at the highest carnitine dose for pregnancy outcomes and comparatively assessed in subfertile, oxidatively stressed mice.

Subjects: "Fertile/healthy" (CD1) and "Subfertile/oxidatively stressed" (gpx5^-/-) mice.

Exposure: Water-soluble micronutrients (vitamin C, zinc, folate, and carnitine).

Intervention: N/A MAIN OUTCOME MEASURES: Sperm parameters included count, motility, viability, and acrosome integrity. Systemic redox status was evaluated in blood, measuring malondialdehyde, thiol levels, and total antioxidant capacity. Sperm DNA parameters were examined for oxidation (8-OHdG staining), fragmentation (TUNEL), and decondensation (toluidine blue). Pregnancy outcomes were also assessed in CD1 mice fed carnitine.

Results: In healthy mice, increasing doses of individual micronutrients had minimal effects on semen parameters. However, high doses of all four micronutrients significantly disrupted the redox balance in blood plasma and compromised sperm DNA integrity in an ingredient-specific manner. Moderate to high doses of carnitine caused severe DNA fragmentation, a finding confirmed in a subsequent experiment using the highest carnitine dose. In this follow-up experiment, male mice supplemented with carnitine and mated with females showed decreased pregnancy rates and fewer total pups born. Conversely, in oxidatively stressed mice, high-dose carnitine had the opposite, beneficial effect of improving sperm DNA integrity.

Conclusions: At high doses, antioxidants can induce reductive stress, damaging vital molecular components of sperm cells such as DNA. Although strong evidence supports the use of preconception antioxidants to boost semen quality, healthcare professionals should assess oxidative stress levels when possible and recommend personalized antioxidant doses to avoid reductive stress and prevent adverse reproductive outcomes.