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<p>Lead (Pb) is a persistent environmental neurotoxicant with particular hazard during developmental periods. This study investigated the mechanistic effects of developmental Pb exposure (100&#xa0;ppm; 5&#xa0;mg/kg/day, administered to dams from GD5–PND14) on maternal neurobiology and reproductive function. All endpoints were assessed in dams’ plasma and tissues collected at PND14. Pb accumulated significantly in the brain, ovary, and uterus, establishing a systemic toxic burden. Exposure induced severe oxidative stress, evidenced by elevated malondialdehyde and depletion of antioxidant defences (CAT, GSH, GST, GR, GPx), alongside increased neuroinflammatory mediators (IL-1β, TGF-β), cholinergic dysregulation, and glial activation (elevated AChE, GFAP, and Iba-1). Cerebral glucose metabolism was markedly impaired, with GLUT-1 overexpression and downregulation of key glycolytic enzymes (HK, PFK-1, PK, G6PD), indicating bioenergetic failure. Pb exposure disrupted the hypothalamic–pituitary axis, reducing GnRH and GnRHR expression while paradoxically elevating Fshβ and Lhβ mRNA and corresponding plasma gonadotropins in dams. Epigenetic dysregulation was characterised by miR-34a upregulation and miR-144 suppression, with pathway enrichment analysis implicating apoptosis, inflammation, and metabolic signalling networks. Collectively, these findings demonstrate that developmental Pb exposure induces convergent oxidative, neuroinflammatory, metabolic, and epigenetic disturbances that underlie dams neuroendocrine and reproductive dysfunction.</p> Graphical Abstract <p>Schematic overview of the study design and integrated mechanistic framework. Pregnant Wistar dams (<i>n</i> = 10/group) received either deionized water (control) or elemental lead suspension (100&#xa0;ppm; 5&#xa0;mg/kg/day, oral gavage) daily from gestational day 5 (GD5) through postnatal day 14 (PND14). At PND14, dams were euthanized and maternal blood, brain, ovary, and uterus/fallopian tube tissues were collected. Pb exposure produced systemic Pb bioaccumulation, plasma and cerebral oxidative stress with antioxidant depletion (CAT, GSH, GST, GR, GPx), neuroinflammation and glial activation (IL-1β, TGF-β, GFAP, Iba-1, AChE), mitochondria-dependent apoptosis (↓Bcl-2, ↑Caspase-3), cerebral bioenergetic reprogramming (↑GLUT-1, ↓HK/PFK-1/PK/G6PD, ↑free glucose), epigenetic dysregulation (↑miR-34a, ↓miR-144), and a paradoxical disruption of the hypothalamic-pituitary–gonadal (HPG) axis characterized by suppressed hypothalamic Kiss1/Kiss1r/GnRH signalling alongside a compensatory pituitary gonadotropin surge (↑FSH, ↑LH) and signs of primary ovarian failure (↓AMH).</p> <p></p>

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Developmental lead exposure fractures the hypothalamic-pituitary–gonadal axis in dams: mechanistic insights into primary ovarian failure and central bioenergetic bottlenecks

  • 期刊论文

  • 发表日期：

    2026年7月16日

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  • Seham Mohammed Abo Zeid,
  • Mohamed O. Mahmoud,
  • Sylvia A. Boshra,
  • Safaa B. Gomaa

摘要

Lead (Pb) is a persistent environmental neurotoxicant with particular hazard during developmental periods. This study investigated the mechanistic effects of developmental Pb exposure (100 ppm; 5 mg/kg/day, administered to dams from GD5–PND14) on maternal neurobiology and reproductive function. All endpoints were assessed in dams’ plasma and tissues collected at PND14. Pb accumulated significantly in the brain, ovary, and uterus, establishing a systemic toxic burden. Exposure induced severe oxidative stress, evidenced by elevated malondialdehyde and depletion of antioxidant defences (CAT, GSH, GST, GR, GPx), alongside increased neuroinflammatory mediators (IL-1β, TGF-β), cholinergic dysregulation, and glial activation (elevated AChE, GFAP, and Iba-1). Cerebral glucose metabolism was markedly impaired, with GLUT-1 overexpression and downregulation of key glycolytic enzymes (HK, PFK-1, PK, G6PD), indicating bioenergetic failure. Pb exposure disrupted the hypothalamic–pituitary axis, reducing GnRH and GnRHR expression while paradoxically elevating Fshβ and Lhβ mRNA and corresponding plasma gonadotropins in dams. Epigenetic dysregulation was characterised by miR-34a upregulation and miR-144 suppression, with pathway enrichment analysis implicating apoptosis, inflammation, and metabolic signalling networks. Collectively, these findings demonstrate that developmental Pb exposure induces convergent oxidative, neuroinflammatory, metabolic, and epigenetic disturbances that underlie dams neuroendocrine and reproductive dysfunction.

Graphical Abstract

Schematic overview of the study design and integrated mechanistic framework. Pregnant Wistar dams (n = 10/group) received either deionized water (control) or elemental lead suspension (100 ppm; 5 mg/kg/day, oral gavage) daily from gestational day 5 (GD5) through postnatal day 14 (PND14). At PND14, dams were euthanized and maternal blood, brain, ovary, and uterus/fallopian tube tissues were collected. Pb exposure produced systemic Pb bioaccumulation, plasma and cerebral oxidative stress with antioxidant depletion (CAT, GSH, GST, GR, GPx), neuroinflammation and glial activation (IL-1β, TGF-β, GFAP, Iba-1, AChE), mitochondria-dependent apoptosis (↓Bcl-2, ↑Caspase-3), cerebral bioenergetic reprogramming (↑GLUT-1, ↓HK/PFK-1/PK/G6PD, ↑free glucose), epigenetic dysregulation (↑miR-34a, ↓miR-144), and a paradoxical disruption of the hypothalamic-pituitary–gonadal (HPG) axis characterized by suppressed hypothalamic Kiss1/Kiss1r/GnRH signalling alongside a compensatory pituitary gonadotropin surge (↑FSH, ↑LH) and signs of primary ovarian failure (↓AMH).