Abstract:
Background Lead is a common neurotoxic substance, and long-term exposure to low-dose lead can cause damage to the nervous system. Previous studies have shown that lead exposure can increase the apoptosis of nerve cells, and damaged nerve cells can not be compensated, which in turn affects the normal function of the brain. In adult mammals, sub-granular zone(SGZ) eventually harbours neural stem cells. Under the stimulation of certain physiological or pathological factors, neural stem cells can proliferate and differentate into neurons and glial cells, and migrate to damaged brain regions to replace damaged cells. Thus new neural circuits are established to maintain the normal functons of the brain. Studies have found that interferon-γ (IFN-γ) can inhibit the proliferation and differentiation of neural stem cells. Transforming growth factor-β (TGF-β) is also a key molecule regulating cell development and cell cycle, and promotes the process of neurogenesis.
Objectve This experiment aims to explore the possible regulatory roles of IFN-γ and TGF-β1 in lead-induced neurogenesis impairment in hippocampal SGZ of rats.
Methods Forty-fve adult male Fisher 344 rats were randomly divided into control group, low-dose lead exposure group, and high-dose lead exposure group. Rats in the low-dose and high-dose lead exposure groups were given 300 mg/L and 600 mg/L lead acetate soluton, respectvely. Rats in the control group were treated with 600 mg/L sodium acetate soluton. The exposure lasted for 9 weeks. Morris water maze test was applied to test the spatal learning and memory ability of the rats. The proliferaton and differentaton of neural stem cells in SGZ were observed by laser scanning confocal microscopy with Ki67+-DCX+ staining. Real-time PCR was used to detect the expressions of Ki67 and DCX mRNA in hippocampal dentate gyrus (DG) region of rats. ELISA assay was used to detect the levels of IFN-γ and TGF-β1 in the hippocampal DG of rats.
Results The blood lead levels in the high-dose and low-dose lead exposure groups were (0.34±0.10) μg/L and (0.19±0.04) μg/L, respectvely, which were higher than that in the control group(0.09±0.03) μg/L. The lead levels in the hippocampal DG area in the highdose and low-dose lead exposure groups were (0.53±0.06) μg/g and (0.48±0.08) μg/g, respectvely, which were also higher than that in the control group(0.40±0.05) μg/g. The neurobehavioral test showed that the escape latencies in the high-dose and low-dose lead exposure groups were (38.37±10.37) s and (31.62±9.24) s, respectvely, which were higher than that in the control group(21.86±6.45) s, and the escape latency in the high-dose lead group was higher than that in the low-dose group (P < 0.05). The average number of crossing platorms in the high-dose lead exposure group was (2.13±0.92) times, which was lower than that in the control group(4.27±1.16) times. The neurons in the hippocampal CA1 area of lead-exposed rats decreased in varying degrees, the arrangement was irregular, and ghost cells and stenotc neurons were observed, especially in the high-dose lead exposure group. The mRNA expression levels of Ki67 and DCX in hippocampal DG region in high-dose lead exposure group were 0.68±0.10 and 0.78±0.12, respectvely, which were lower than the levels in the control group (both were 1.00±0.16). The rato of SGZ (Ki67+-DCX+)/Ki67+ in the high-dose lead exposure group was 56.4% (20.87% vs. 37.00%) in the control group, and it was also lower than the low-dose lead exposure group, which was 61.2% (20.87% vs. 34.11%), showing signifcant difference (P < 0.05). The expression level of IFN-γ in hippocampal DG area of rats with high-dose lead exposure and low-dose lead exposure were(1.22±0.09) ng/mg (in terms of protein, thereafter) and (1.20±0.11) ng/mg, which were higher than the level of the control group(1.08±0.08)ng/mg, showing signifcant difference (P < 0.05). The expression levels of TGF-β1 in hippocampal DG of the high-dose and lowdose lead exposure groups were (3.15±0.24) ng/mg and (3.36±0.32) ng/mg, respectvely, which were lower than that of the control group(3.65±0.37)ng/mg, showing signifcant difference (P < 0.05).
Conclusion Lead exposure may increase the level of IFN-γ, inhibit the expression level of TGF-β1, affect the differentaton of neural stem cells, and result in the decrease of newborn neurons in lead exposure rats. The damaged neurons can not be compensated, which may be the reason for the decline of learning and memory ability in adult rats with neurobehavioral changes.
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