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Association of Atrazine-Induced Overexpression of Aldo–Keto-Reductase 1C2 (AKR1C2) with Hypoandrogenism and Infertility: An Experimental Study in Male Wistar Rat

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Abstract

Atrazine (ATZ, C8H14ClN5) is a widely used synthetic herbicide that contaminates drinking water. It is a known endocrine disruptor that disrupts various molecular pathways involved in hormone signaling, and DNA damage, and can cause reproductive disorders, including decreased fertility, and abnormal development of reproductive organs, as revealed in animal model studies. However, the effect of ATZ on steroidogenesis in the male reproductive system, especially reduction of ketosteroids to hydroxysteroids, remains unclear. This study investigated the toxicity of ATZ on the male reproductive system in the Wistar rat model, with an emphasis on its adverse effect on aldo-ketoreductase family 1 member C2 (AKR1C2). Male Wistar rats were administered ATZ for 56 days (duration of one spermatogenic cycle) through oral route, at 20, 40 and 60 mg/kg body weight (bw) doses. The results indicate that ATZ exposure affects the body weight, impairs sperm production, and decrease FSH, LH, and testosterone levels. Additionally, the down-regulation of key steroidogenic enzymes by ATZ disrupted the synthesis of testosterone, leading to decreased levels of this essential male hormone. On the other hand, the expression of AKR1C2 (mRNA and protein) in the testis was upregulated. The findings suggest that AKR1C2 plays a role in androgen metabolism. Furthermore, its overexpression may lead to alteration in the expression of genes in the connected pathway, causing an increase in the breakdown or inactivation of androgens, which would result in lower androgen levels and, thereby, lead to hypoandrogenism, as the combined effects of down-regulation of steroidogenic genes and up-regulation of AKR1C2. These findings reveal direct implication of disrupted AKR1C2 in male reproductive health and highlight the need for further research on the impact of environmental toxins on human fertility, ultimately providing for better patient care.

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Funding

This study was supported by the National Higher Education Mission (RUSA), 2.0:- Biological Sciences; Tamil Nadu State Council for Higher Education (TANSCHE); and Department of Science and Technology Teachers Associateship for Research Excellence (DST-TARE). National Centre for Alternatives to Animal Experiments (NCAAE), and DST-FIST at Department of Animal Science, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India, provided the infrastructure for the execution of this research.

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  1. Department of Animal Science, Bharathidasan University, Tiruchirappalli, 620024, Tamil Nadu, India

    Angel Mary Arulanandu, Vignesh Kalimuthu, Swathi Chandran Manimegalai, Ramya Venkatesan, Sathiya Priya Krishnamoorthy & Kadalmani Balamuthu

  2. Research Coordinator & Department of Biotechnology, Bioinformatics and Microbiology, National College (Autonomous), Tiruchirappalli, 620001, Tamil Nadu, India

    Akbarsha Mohammad Abdulkader

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Arulanandu, A.M., Kalimuthu, V., Manimegalai, S.C. et al. Association of Atrazine-Induced Overexpression of Aldo–Keto-Reductase 1C2 (AKR1C2) with Hypoandrogenism and Infertility: An Experimental Study in Male Wistar Rat. Reprod. Sci. 31, 3228–3239 (2024). https://doi.org/10.1007/s43032-024-01627-3

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