الفهرس 
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Abstract
Lithium salts serve as mood-stabilizing and psychotropic agents in patients with bipolar disorders (BDs), mania, and chronic depression. However, lithium completely penetrates the placenta and is transferred through lactation, causing several perinatal complications, including low birth weight, congenital diseases, neonatal deformation, intrauterine growth restriction, and vascular defects. Thus, the current study was designed to recognize the effect of maternal administration of lithium chloride (LiCl) on the neuroendocrine-cytokine, and thyroid-cerebral axes in neonatal albino rats, particularly at postnatal days (PNDs) 14, 21, and 28. Thus, thirty-six pregnant Wistar rats (Rattus norvegicus) weighting 160-180 g were allocated into two groups as the following:
1-) LiCl-treated group: Eighteen pregnant rats were orally administered 50 mg LiCl/kg b.wt. by gastric intubations from gestational day (GD) 1 to lactation day (LD) 28.
2-) Control group: Eighteen pregnant rats were orally administered saline only as a vehicle from GD 1 to LD28.
The body weight of the pregnant rats was observed at the beginning and before scarification at LDs 14, 21, and 28. Also, the neonatal body weight was monitored before scarification at PNDs 14, 21, and 28. The abortion and mortality were followed during the experimental period. Anesthetized dams or neonates by mild diethyl ether were sacrificed, and blood samples were collected from their jugular vein at examined days. The centrifugation of the coagulated blood was at 3000 rpm (1006.2 g) for 20 minutes, and the clear supernatants were recollected in Eppendorf tubes and stored at -20°C for the biochemical ELISA (enzyme-linked immunosorbent assay) investigations. On the other hand, the maternal and neonatal thyroid gland, and neonatal cerebrum were isolated immediately and dropped into the chosen fixative for the general histopathological alterations. Moreover, the neonatal cerebral tissues were perfused and homogenized in ice-cold phosphate-buffered saline (PBS) (10% wt/vol) or acidified n-butanol for subsequent spectrophotometric and spectrofluorometric investigations, respectively. The remaining cerebral tissues were reserved at -70 °C for subsequent quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assay. Thus, the obtained data from the current experimental work revealed the following:
1. The maternal administration of LiCl disrupted the histological structure of the maternal and neonatal thyroid gland at LDs 14, 21, and 28. There was a follicular dilatation with massive colloid and flattened lining epithelium, follicular epithelial hyperplasia, thyrocyte detachment, hyperemia, follicular lumen obliteration, and colloidal vacuolation in the maternal thyroid gland during the experimental period. On the other hand, this maternal administration showed a focal lining epithelium rupture or degeneration, detaching follicular cells in the lumen of some follicles, and cytoplasmic or colloidal vacuolation in the neonatal thyroid gland at PNDs 14, 21, and 28.
2. This administration also induced hypothyroidism in both dams and their neonates at LDs 14, 21, and 28. The hypothyroid state was illustrated by an elevation in the thyrotropin (TSH) level paralleled by a profound decline in free thyroxin (FT4) and free triiodothyronine (FT3) levels in comparison with the corresponding levels in control dams and their neonates.
3. Maternal LiCl produced undesirable effects on maternal/neonatal body weight and survival of dams/pups. An abortion was recorded in one case at GD 17, while neonatal mortality was observed in 3 cases at birth. In addition, a reduction in the gain of maternal and neonatal body weight was observed on all examined LDs compared to those of the control group. The deterioration in the neonatal body weight gain in the maternal LiCl-treated group might be explained by the reduction in the neonatal serum growth hormone (GH), elevation in the neonatal serum leptin, and disturbance in the neonatal serum adiponectin and resistin levels.
4. Maternal LiCl perturbed the levels of neonatal serum tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), interleukin-1 beta (IL-1β), and transforming growth factor-beta (TGF-β). The levels of TNF-α and TGF-β were highly considerably increased in the neonates of the maternal LiCl-treated group at all tested PNDs. The elevation in the IL-1β level was non-significant at PNDs 14 and 28 and highly significant at PND 21 in the maternal LiCl-treated group concerning the control group. Although the level of IFN-γ was non-significantly decreased at PND 14, its level was highly significantly increased at PNDs 21 and 28 in the maternal LiCl-treated group compared to the control group.
5. Maternal LiCl also induced some histopathological alterations in the neonatal cerebral cortex at PNDs 14, 21, and 28. There was gliosis, neural degeneration, vacuolations, nuclear pyknosis, karyolysis, hyperemia, and oedema. These alterations could be attributed to the imbalance in the neonatal cerebral prooxidants-antioxidants axis. where the levels of malondialdehyde (MDA), nitric oxide (NO), and hydrogen peroxide (H2O2) were elevated, and the levels of total thiol (t-SH), glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) were decreased at all examined PNDs compared to the control group.
6. The hypothyroid state in both dams and their neonates due to maternal administration of LiCl produced fluctuating effects on monoamine levels in the cerebrum of neonates. The level of neonatal cerebral serotonin (5-HT) was significantly elevated, while the levels of neonatal cerebral dopamine (DA) and norepinephrine (NE) were highly significantly decreased at PND 14. Although a reduction in the 5-HT and DA levels was observed, a negligible increase in the NE level was recorded at PNDs 21 and 28 compared to the control group. The reduction in the 5-HT level of the maternal LiCl-treated group at PNDs 21 and 28 might be correlated with the elevation in the leptin level on the same examined days.
7. In the maternal LiCl-treated group, the fold change in the expression of iodothyronine deiodinase II (DII) mRNA in the neonatal cerebrum showed a non-significant increase at PND 14, a highly significant elevation at PND 21, and a non-significant decrease at PND 28 compared to the control group. While a highly significant elevation in the fold change of iodothyronine deiodinase III (DIII) mRNA was noticed at PND 14, a non-significant increase in its fold was recorded at PNDs 21 and 28 compared to the control group. Hence, LiCl disrupts the neonatal cerebral DII and DIII, which are essential for determining the available T3 during development. This disturbance could be attributed to oxidative stress and hypothyroidism in neonates due to the maternal administration of LiCl.
In conclusion, the maternal administration of LiCl to mothers may cause several anomalies in the development of their newborns and may lead to a pathophysiological state. This administration may act as a disruptor for the neonatal neuroendocrine-cytokine and thyroid-cerebrum axes, thus initiating a stress state in both dams and their neonates. This status may distort the communication between dams and their offspring, resulting in neonatal neurodevelopmental disorder.