ZIP9-centered pathway compensates for radiofrequency radiation-mediated reduction in resistance to H2O2 damage in Sertoli cells of rats

Abstract

ZIP9-centered pathway compensates for radiofrequency radiation-mediated reduction in resistance to H2O2 damage in Sertoli cells of rats Yu G, Zhu Y, Song C, Chen L, Tang Z, Wu T. The ZIP9-centered androgen pathway compensates for the 2605 MHz radiofrequency electromagnetic radiation-mediated reduction in resistance to H2O2 damage in Sertoli cells of adult rats. Ecotoxicol Environ Saf. 2023 Mar 6;254:114733. doi: 10.1016/j.ecoenv.2023.114733 Highlights • RF-EMR suppress ability of sertoli cells to resist external insults. • Testosterone reversed reduction of resistence ability of sertoli cells exposed to RF-EMR. • Testosterone exerted its compensatory effect via ZIP9 in sertoli cells. • Unfolding protein response involved in testosterone-ZIP9 mediated compensatory effects. • Testosterone-ZIP9 mediated effect might gradually weared off with exposure time prolonged. Abstract The direct biological effects of radiofrequency electromagnetic radiation (RF-EMR) from wireless communication equipment on the testes are still unclear. Our previous study proved that long-term exposure to 2605 MHz RF- EMR gradually damage spermatogenesis and resulted in time-dependent reproductive toxicity by directly disrupting blood-testis barrier circulation. Although short-term exposure did not cause readily observable damage to fertility, whether it caused specific biological effects and how these effects contributed to the time- dependent reproductive toxicity of RF-EMR were currently unknown. Studies on this issue are important for elucidating the time-dependent reproductive toxicity of RF-EMR. The present study established a 2605 MHz RF- EMR (SAR=1.05 W/Kg) scrotal exposure model with rats and extracted primary Sertoli cells for exposure to investigate the direct biological effects of short-term RF-EMR exposure on the testis. The results showed that short-term RF-EMR exposure did not decrease sperm quality and spermatogenesis, but it increased the levels of testicular testosterone (T) and zinc transporter 9 (ZIP9) in Sertoli cells of rats. In vitro, 2605 MHz RF-EMR exposure did not increase the apoptosis rate of Sertoli cells, but it increased the apoptosis rate and MDA of Sertoli cells exposed to H2O2. T reversed these changes and increased ZIP9 level in Sertoli cells, whereas inhibiting ZIP9 expression significantly suppressed these T-mediated protective effects. Moreover, T increased the levels of phosphorylated inositol-requiring enzyme 1 (P-IRE1), phosphorylated protein kinase R (PKR)-like endoplasmic reticulum kinase (P-PERK), phosphorylated eukaryotic initiation factor 2a (P-eIF2a) and phosphorylated activating transcription factor 6 (P-ATF6) in Sertoli cells, and these effects were reversed by ZIP9 inhibition. With prolonged exposure time, testicular ZIP9 was gradually downregulated, and testicular MDA increased. ZIP9 level was negatively correlated with MDA level in the testes of exposed rats. Thus, although short-term exposure to 2605 MHz RF-EMR (SAR=1.05 W/kg) did not significantly disturb spermatogenesis, it suppressed the ability of Sertoli cells to resist external insults, which was rescued by enhancing the ZIP9- centered androgen pathway in the short term. Increasing the unfolded protein response might be an important downstream mechanism involved. These results promote a better understanding of the time-dependent reproductive toxicity of 2605 MHz RF-EMR. pubmed.ncbi.nlm.nih.gov

AI evidence extraction

Main findings

Short-term 2605 MHz RF-EMR (SAR 1.05 W/kg) did not decrease sperm quality or spermatogenesis, but increased testicular testosterone and ZIP9 in Sertoli cells. In vitro, RF-EMR did not increase Sertoli cell apoptosis alone, but increased apoptosis and MDA when cells were challenged with H2O2; testosterone reversed these changes via a ZIP9-dependent mechanism and was associated with increased unfolded protein response markers. With prolonged exposure time, testicular ZIP9 was downregulated and MDA increased, with a negative correlation between ZIP9 and MDA.

Outcomes measured

• Sperm quality
• Spermatogenesis
• Testicular testosterone levels
• ZIP9 levels in Sertoli cells/testis
• Sertoli cell apoptosis (baseline and with H2O2 challenge)
• Malondialdehyde (MDA) levels
• Unfolded protein response markers (P-IRE1, P-PERK, P-eIF2a, P-ATF6)
• Correlation between ZIP9 and MDA

Limitations

• Exposure duration details not specified in the abstract
• Sample size not reported in the abstract
• Findings include both in vivo rat scrotal exposure and in vitro primary Sertoli cell experiments, limiting direct inference to human health

Suggested hubs

• 5g-policy (0.2)
  Uses 2605 MHz RF exposure (a frequency used in some cellular bands), but the paper is mechanistic/toxicology rather than policy.

{
    "study_type": "animal",
    "exposure": {
        "band": "RF",
        "source": "wireless communication equipment",
        "frequency_mhz": 2605,
        "sar_wkg": 1.0500000000000000444089209850062616169452667236328125,
        "duration": "short-term (also mentions prolonged exposure time in results)"
    },
    "population": "Adult rats; primary Sertoli cells (in vitro)",
    "sample_size": null,
    "outcomes": [
        "Sperm quality",
        "Spermatogenesis",
        "Testicular testosterone levels",
        "ZIP9 levels in Sertoli cells/testis",
        "Sertoli cell apoptosis (baseline and with H2O2 challenge)",
        "Malondialdehyde (MDA) levels",
        "Unfolded protein response markers (P-IRE1, P-PERK, P-eIF2a, P-ATF6)",
        "Correlation between ZIP9 and MDA"
    ],
    "main_findings": "Short-term 2605 MHz RF-EMR (SAR 1.05 W/kg) did not decrease sperm quality or spermatogenesis, but increased testicular testosterone and ZIP9 in Sertoli cells. In vitro, RF-EMR did not increase Sertoli cell apoptosis alone, but increased apoptosis and MDA when cells were challenged with H2O2; testosterone reversed these changes via a ZIP9-dependent mechanism and was associated with increased unfolded protein response markers. With prolonged exposure time, testicular ZIP9 was downregulated and MDA increased, with a negative correlation between ZIP9 and MDA.",
    "effect_direction": "mixed",
    "limitations": [
        "Exposure duration details not specified in the abstract",
        "Sample size not reported in the abstract",
        "Findings include both in vivo rat scrotal exposure and in vitro primary Sertoli cell experiments, limiting direct inference to human health"
    ],
    "evidence_strength": "low",
    "confidence": 0.7800000000000000266453525910037569701671600341796875,
    "peer_reviewed_likely": "yes",
    "keywords": [
        "radiofrequency electromagnetic radiation",
        "RF-EMR",
        "2605 MHz",
        "SAR 1.05 W/kg",
        "scrotal exposure",
        "rat",
        "testis",
        "Sertoli cells",
        "spermatogenesis",
        "testosterone",
        "ZIP9",
        "oxidative stress",
        "H2O2",
        "MDA",
        "unfolded protein response"
    ],
    "suggested_hubs": [
        {
            "slug": "5g-policy",
            "weight": 0.200000000000000011102230246251565404236316680908203125,
            "reason": "Uses 2605 MHz RF exposure (a frequency used in some cellular bands), but the paper is mechanistic/toxicology rather than policy."
        }
    ]
}

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