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<p>Acrylamide (ACR), a prevalent dietary toxicant formed in thermally processed foods via the Maillard reaction, is known to cross the placental barrier. While ACR-induced reproductive and developmental toxicity has been reported, the protective role of melatonin (MTN) via modulation of the <i>SHH/GLI3</i> signaling pathway remains unclear. Pregnant Balb/c mice were divided into three groups (n = 6/group): control (distilled water), ACR (50&#xa0;mg/kg/d), and ACR (50&#xa0;mg/kg/d) + MTN (10&#xa0;mg/kg/d), treated orally from gestational day (GD) 3.5 to GD 13.5. Placentas and embryos were collected for analysis. Oxidative stress (MDA levels), VEGF expression, and <i>SHH/GLI3</i> pathway activity were assessed using immunohistochemistry and qRT-PCR. ACR exposure induced significant embryotoxicity, manifested as a 34% reduction in fetal weight (1.60 ± 0.09&#xa0;g vs. 1.88 ± 0.14&#xa0;g in controls, <i>p</i>&#xa0;&lt;&#xa0;0.001) and a 46.2% reduction in fetal crown-rump length (0.7 ± 0.08&#xa0;cm vs. 1.1 ± 0.1&#xa0;cm, <i>p</i>&#xa0;&lt;&#xa0; 0.001). MTN co-treatment significantly ameliorated these growth restrictions. IHC analysis revealed that ACR significantly reduced SHH protein expression in the embryonic intestine and liver (<i>p</i> &lt;&#xa0;0.01), while it increased GLI3 protein levels (<i>p</i>&#xa0;&lt;&#xa0;0.01). MTN effectively normalized the expression of both proteins. At the molecular level, ACR downregulated <i>SHH</i> expression (<i>p</i> &lt;&#xa0; 0.001) and upregulated <i>GLI3</i> (<i>p</i>&#xa0;&lt; &#xa0;0.01), which were reversed by MTN. ACR exposure significantly increased oxidative stress (105% increase in placental MDA, <i>p</i>&#xa0;&lt;&#xa0; 0.001) and reduced placental VEGF expression by 69.3% (<i>p</i>&#xa0;&lt;&#xa0; 0.0001), both of which were significantly mitigated by MTN co-treatment. These integrated findings demonstrate that MTN exerts potent antioxidative and cytoprotective effects by mitigating ACR-induced oxidative stress, restoring <i>SHH/GLI3</i> protein and gene expression, preserving VEGF-mediated placental angiogenesis, and preventing morphological defects. Our results underscore MTN’s therapeutic potential in counteracting ACR-induced teratogenicity and supporting healthy organogenesis.</p>

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Melatonin modulates SHH/GLI3 signaling and placental angiogenesis to counter acrylamide embryotoxicity

  • 期刊论文

  • 发表日期：

    2025年10月15日

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  • Reyhane Vardiyan,
  • Daniyal Ezati,
  • Mehdi jalali,
  • Farzaneh Vafaee,
  • Shabnam Mohammadi

摘要

Acrylamide (ACR), a prevalent dietary toxicant formed in thermally processed foods via the Maillard reaction, is known to cross the placental barrier. While ACR-induced reproductive and developmental toxicity has been reported, the protective role of melatonin (MTN) via modulation of the SHH/GLI3 signaling pathway remains unclear. Pregnant Balb/c mice were divided into three groups (n = 6/group): control (distilled water), ACR (50 mg/kg/d), and ACR (50 mg/kg/d) + MTN (10 mg/kg/d), treated orally from gestational day (GD) 3.5 to GD 13.5. Placentas and embryos were collected for analysis. Oxidative stress (MDA levels), VEGF expression, and SHH/GLI3 pathway activity were assessed using immunohistochemistry and qRT-PCR. ACR exposure induced significant embryotoxicity, manifested as a 34% reduction in fetal weight (1.60 ± 0.09 g vs. 1.88 ± 0.14 g in controls, p < 0.001) and a 46.2% reduction in fetal crown-rump length (0.7 ± 0.08 cm vs. 1.1 ± 0.1 cm, p <  0.001). MTN co-treatment significantly ameliorated these growth restrictions. IHC analysis revealed that ACR significantly reduced SHH protein expression in the embryonic intestine and liver (p < 0.01), while it increased GLI3 protein levels (p < 0.01). MTN effectively normalized the expression of both proteins. At the molecular level, ACR downregulated SHH expression (p <  0.001) and upregulated GLI3 (p <  0.01), which were reversed by MTN. ACR exposure significantly increased oxidative stress (105% increase in placental MDA, p <  0.001) and reduced placental VEGF expression by 69.3% (p <  0.0001), both of which were significantly mitigated by MTN co-treatment. These integrated findings demonstrate that MTN exerts potent antioxidative and cytoprotective effects by mitigating ACR-induced oxidative stress, restoring SHH/GLI3 protein and gene expression, preserving VEGF-mediated placental angiogenesis, and preventing morphological defects. Our results underscore MTN’s therapeutic potential in counteracting ACR-induced teratogenicity and supporting healthy organogenesis.