Effects of gestational hypothyroidism on mouse brain development: Gabaergic systems and oxidative stress

Dev Biol. 2024 Nov:515:112-120. doi: 10.1016/j.ydbio.2024.07.010. Epub 2024 Jul 22.

Abstract

Hormonal imbalance during pregnancy is a risk factor for neuropsychiatric impairment in the offspring. It has been suggested that hypothyroidism leads to dysfunction of cortical GABAergic interneurons and inhibitory system development that in turn underlies impairment of the central nervous system. Here we investigated how gestational hypothyroidism affected offspring GABAergic system development as well as redox regulation parameters, because of previous links identified between the two. Experimental Gestational Hypothyroidism (EGH) was induced in CD-1 mice with 0.02% methimazole (MMI) in drinking water from embryonic day 9 (E9) until tissue collection at embryonic day 14 (E14) or E18. We examined GABAergic cell distribution and inhibitory system development gene expression as well as redox relevant gene expression and direct measures across all embryos regardless of sex. Intrauterine restriction of maternal thyroid hormones significantly impacted both of these outcomes in brain, as well as altering redox regulation in the placenta. GAD67+ neuronal migration was reduced, accompanied by a disruption in gene expression influencing GABAergic cell migration and cortical inhibitory neural system development. EGH also altered embryonic brain gene expression of Gpx1, Nfe2l2, Cat levels in the dorsal E14 brains. Additionally, EGH resulted in elevated TBARS, Gpx1 and Nfe2l2 in the ventral E18 brains. Furthermore, EGH downregulated placental Gpx1 gene expression at E14 and increased protein oxidation at E18. These findings support the hypothesis that sufficient maternal thyroid hormone supply to the fetus influences central nervous system development, including processes of GABAergic system development and redox equilibrium.

Keywords: Central nervous system; Fetal programming; GABAergic system; Gestational hypothyroidism; Oxidative stress.

MeSH terms

  • Animals
  • Brain* / embryology
  • Brain* / metabolism
  • Cell Movement
  • Female
  • GABAergic Neurons* / metabolism
  • Gene Expression Regulation, Developmental / drug effects
  • Glutamate Decarboxylase / genetics
  • Glutamate Decarboxylase / metabolism
  • Glutathione Peroxidase GPX1*
  • Glutathione Peroxidase* / genetics
  • Glutathione Peroxidase* / metabolism
  • Hypothyroidism* / metabolism
  • Male
  • Methimazole
  • Mice
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism
  • Oxidative Stress*
  • Placenta / metabolism
  • Pregnancy
  • Prenatal Exposure Delayed Effects / metabolism
  • Thyroid Hormones / metabolism

Substances

  • Glutathione Peroxidase GPX1
  • Glutathione Peroxidase
  • Methimazole
  • Gpx1 protein, mouse
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • glutamate decarboxylase 1
  • Glutamate Decarboxylase
  • Thyroid Hormones