A groundbreaking study led by researchers at Toho University has unveiled a novel biological mechanism through which docosahexaenoic acid (DHA), a principal component of omega-3 fatty acids predominantly found in fish oil, exerts a direct and selective relaxant effect on smooth muscle tissue within the male reproductive system. This discovery sheds compelling light on the intricate molecular interactions underpinning male reproductive physiology and proposes an innovative therapeutic pathway for addressing ejaculatory duct obstruction, a significant contributor to male infertility. Their findings were published in the esteemed journal Biological and Pharmaceutical Bulletin, marking a pivotal advancement in our understanding of DHA’s multifaceted health benefits.
The research delves into the contractile dynamics of the vas deferens, a muscular conduit critical for propelling spermatozoa during ejaculation. Under physiological conditions, noradrenaline, a catecholamine neurotransmitter, activates α_1A-adrenoceptors located on smooth muscle cells of the vas deferens. This receptor stimulation triggers the influx of calcium ions through distinct channels, predominantly L-type voltage-dependent calcium channels (VDCC) and non-selective cation channels known as transient receptor potential canonical (TRPC) channels, specifically TRPC3 and TRPC6 subtypes. The precise orchestration of calcium entry through these channels orchestrates the contraction necessary for semen transport.
Employing a series of meticulous in vitro experiments on rat vas deferens tissue, the team discovered that acute application of DHA selectively inhibits the calcium influx mediated by TRPC3/6 channels without substantially affecting the L-type VDCC pathway. This selectivity culminates in a pronounced reduction of the “fast” or phasic contraction component evoked by noradrenaline. The implication of this mechanistic insight is profound, suggesting that DHA disrupts a critical signaling axis responsible for rapid smooth muscle contraction through modulating TRPC channel activity, thereby attenuating vas deferens contractility.
Importantly, the study highlights the tissue-specific nature of DHA’s action. Contrasting the vas deferens, contractile responses in prostate tissue—another site rich in smooth muscle but differing in calcium channel expression profile—remained unaltered by DHA treatment. This specificity marks a significant discovery, suggesting that the bioactivity of DHA is tightly linked to the molecular architecture of targeted tissues, conferring a degree of precision to its physiological effects and reinforcing the notion of TRPC channels as pivotal modulators in reproductive smooth muscle function.
Calcium signaling pathways are fundamental to muscular excitation-contraction coupling, and modulation of such channels represents a strategic target for pharmacological intervention. By demonstrating that DHA preferentially suppresses TRPC3/6 channel-mediated calcium entry, this study not only elucidates a previously uncharacterized action of omega-3 fatty acids but also positions these lipid mediators as potential modulators of male reproductive health. The findings introduce the exciting possibility that dietary or supplemental DHA can influence reproductive physiology beyond its established roles in neural and cardiovascular systems.
From a pathophysiological perspective, the ability of DHA to reduce intraluminal pressure within the vas deferens could alleviate mechanical barriers encountered in ejaculatory duct obstruction. Such obstructions impede sperm transport and are implicated in certain forms of male infertility. Therapeutic modulation of TRPC channel activity by DHA or DHA-derived analogs may, therefore, represent a novel non-invasive strategy to enhance sperm delivery and fertility outcomes, circumventing the need for surgical interventions.
At the molecular level, the inhibition of TRPC3/6 channels by DHA suggests an interaction between this polyunsaturated fatty acid and specific membrane or channel protein domains that regulate ion conductance. While the precise binding sites and conformational changes remain to be delineated, the study points to a nuanced modulation of channel gating mechanisms by DHA, possibly through altering lipid microenvironments or direct channel interactions, which warrants further biophysical and pharmacological exploration.
Moreover, the differential modulation of calcium entry pathways observed underscores the complexity of TRPC channel regulation within smooth muscle cells. TRPC channels, integral to receptor-operated calcium entry, often operate in concert with voltage-dependent channels to finely tune contractile responses. DHA’s preferential inhibition of TRPC3/6 channels delineates a selective pharmacological profile which, unlike broad-spectrum calcium channel blockers, may preserve essential L-type channel function while mitigating hypercontractility.
The broader implications extend beyond male fertility. Given the ubiquitous presence of TRPC channels in diverse smooth muscle tissues, including those of the vascular and gastrointestinal systems, understanding the interaction of DHA with these channels may illuminate new avenues for managing conditions characterized by aberrant smooth muscle contractility, such as hypertension or spastic disorders. Nonetheless, the reproductive system-specific effects identified by this study highlight potential for targeted therapeutic development.
Another dimension of the research pertains to the translational relevance of the experimental findings. The concentrations of DHA that produced significant inhibition of TRPC-mediated contraction align with plasma levels achievable through conventional dietary supplementation. This correlation strengthens the prospect of practical application and supports ongoing recommendations endorsing omega-3 fatty acid intake for health maintenance, potentially encompassing reproductive function enhancement.
Dr. Keisuke Obara, lead investigator and associate professor at Toho University, emphasizes the significance of these discoveries: “Our findings establish TRPC3/6 channels as molecular targets of DHA in reproductive smooth muscle, providing a mechanistic framework that could rationalize DHA’s broader physiological effects. This paves the way for developing novel dietary or pharmacological interventions aimed at male reproductive health, among other clinical areas.”
Future investigations are poised to explore the clinical translatability of these results through human studies and the expansion of experimental models. Such research will seek to verify the efficacy and safety of DHA supplementation in managing male infertility associated with ejaculatory dysfunction and explore the impact of chronic DHA intake on reproductive outcomes. Additionally, the molecular characterization of DHA-channel interactions remains a fertile ground for further scientific inquiry.
In conclusion, this seminal research illuminates the potent and selective bioactivity of DHA within male reproductive smooth muscle, mediated through inhibition of TRPC3/6 calcium channels. It enriches the understanding of omega-3 fatty acids’ systemic roles and initiates a promising trajectory toward novel, mechanistically grounded therapeutics for male reproductive disorders, all while reaffirming the multifaceted beneficial influence of dietary DHA in human health.
Subject of Research: Animals (rat vas deferens smooth muscle)
Article Title: Docosahexaenoic acid targets TRPC3/6 channels to suppress noradrenaline-induced contraction in rat vas deferens smooth muscle
News Publication Date: 30-Sep-2025
Web References: http://dx.doi.org/10.1248/bpb.b25-00428
References:
Obara K, Enomoto M, Furuta M, Okura H, Kato A, Mouri T, Gohara M, Ura T, Nasu H, Yoshioka K, Kusakabe T, Takahashi K, Kato K, Tanaka Y. Docosahexaenoic acid targets TRPC3/6 channels to suppress noradrenaline-induced contraction in rat vas deferens smooth muscle. Biological and Pharmaceutical Bulletin. 2025 Sep 30.
Image Credits: Keisuke Obara
Keywords: DHA, docosahexaenoic acid, omega-3 fatty acids, smooth muscle relaxation, vas deferens, TRPC3/6 channels, calcium influx, noradrenaline, male reproductive health, ejaculatory duct obstruction, male infertility, L-type VDCC
