Redox Homeostasis and Nrf2-Regulated Mechanisms Are Relevant to Male Infertility

Abstract

Infertility represents a significant global health challenge, affecting more than 12% of couples worldwide, and most cases of infertility are caused by male factors. Several pathological pathways are implicated in male infertility. The main mechanisms involved are driven by the loss of reduction-oxidation (redox) homeostasis and the resulting oxidative damage as well as the chronic inflammatory process. Increased or severe oxidative stress leads to sperm plasma membrane and DNA oxidative damage, dysregulated RNA processing, and telomere destruction. The signaling pathways of these molecular events are also regulated by Nuclear factor-E2-related factor 2 (Nrf2). The causes of male infertility, the role of oxidative stress in male infertility and the Keap1-Nrf2 antioxidant pathway are reviewed. This review highlights the regulatory role of Nrf2 in the balance between oxidants and antioxidants as relevant mechanisms to male fertility. Nrf2 is involved in the regulation of spermatogenesis and sperm quality. Establishing a link between Nrf2 signaling pathways and the regulation of male fertility provides the basis for molecular modulation of inflammatory processes, reactive oxygen species generation, and the antioxidant molecular network, including the Nrf2-regulated antioxidant response, to improve male reproductive outcomes.

Keywords: human male infertility; nuclear factor-E2-related factor 2 (Nrf2); oxidative stress; sperm.

Figure 1

A schematic human spermatozoon. Human spermatozoon comprises three main sections: head, midpiece, and tail. The structures that characterize each region are indicated. The acrosome is located in the apical part of the nucleus and contains lytic enzymes; the nucleus is characterized by highly condensed chromatin; the equatorial segment is located at the end of acrosome. From the centriole the axoneme originates, the mitochondria surround the axoneme in the midpiece.

Figure 2

The structural domains of Nrf2 (A) and Keap1 (B). (A): Nrf2 comprises seven Nrf2-ECH homeodomains (Neh). For each Neh domain, the specific activity is indicated. (B): Keap1 has five domains, including NTR (N-terminal region), BTB (Bric a brac, tramtrack and broad complex), IVR (intervening region), Kelch (Kelch or DGR domains) and CTR (C-terminal region). The specific role is indicated for each region. The amino acid residues for each domain are indicated in red.

Figure 3

The Nrf2 antioxidative pathway. Activation of the Nrf2 transcription factor in oxidative conditions led to upregulation of Nrf2-related gene expression and reduction in reactive oxygen species (ROS). In normal conditions, ubiquitination of Nrf2 leads to proteasomal degradation. ARE, antioxidant response element; Nrf2, nuclear erythroid-factor-2; SOD, Superoxide Dismutase; CAT, Catalase; GPx, Glutathione Peroxidase, NQO1, quinone oxidoreductase-1; HO-1, heme oxygenase-1; sMAF, small musculoaponeurotic fibrosarcoma oncogene homolog, Ub: ubiquitin.

Figure 4

Nrf2 roles in male fertility. Nrf2 is a regulator of multiple mechanisms involved in the adequate production and maturation of sperm. The figure summarizes the main roles of Nrf2 in the regulation of male fertility. Further details and bibliographical references are given in Section 4.