Mustafa Amjad, Holladay Steven, Witonsky Sharon, Zimmerman Kurt, Manari Ashley, Countermarsh Sheryl, Karpuzoglu Ebru, Gogal Robert
Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Tech, Blacksburg, Virginia, USA.
Birth Defects Res B Dev Reprod Toxicol. 2011 Feb;92(1):82-94. doi: 10.1002/bdrb.20285.
Prenatal exposure to the persistent environmental pollutant and model Ah receptor agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), has been shown to permanently suppress postnatal cell-mediated immunity. More recently, skewing of select adult T and B cell responses toward enhanced inflammation has also been described in C57BL/6 mice after prenatal TCDD. This raises questions about adverse postnatal immune consequences of prenatal TCDD in animals genetically predisposed to inappropriate inflammatory responses.
Lupus-prone SNF(1) mice were exposed to 0, 40, or 80 µg/kg TCDD on gestation day (gd) 12 and examined at 36 weeks-of-age for immunomodulatory effects that correlated with worsened lupus pathology.
Bone marrow pro- and large pre-B cells were decreased by prenatal TCDD, in both adult male and female mice, as were pre- and immature B cells. Splenic CD23(-) CD1(hi) and CD19(+) CD5(+) B cells were increased in males, as were B220(hi) B cells in females, further suggesting persistent disruption of B cell lymphopoiesis by prenatal TCDD. Female mice displayed decreased IL-10 production by ConA-activated splenocytes, while males underproduced IL-4. Autoreactive CD4(+) Vβ17a(+) spleen T cells were increased in both sexes by 80 µg/kg TCDD. Male mice but not females showed increased anti-ds DNA and cardiolipin autoantibody levels.
Prenatal TCDD augmented the hallmark indicators of SLE progression in the lupus-prone SNF(1) mice, including renal immune complex deposition, glomerulonephritis, and mesangial proliferation. Prenatal TCDD therefore caused persistent modulation of the postnatal immune response, and exacerbated inflammatory disease, in lupus-like autoimmune SNF(1) mice.
产前暴露于持久性环境污染物及典型芳烃受体激动剂2,3,7,8 - 四氯二苯并 - 对 - 二恶英(TCDD)已被证明会永久性抑制产后细胞介导的免疫。最近,在产前接触TCDD的C57BL / 6小鼠中也描述了特定成年T细胞和B细胞反应向增强炎症方向的偏移。这引发了关于产前TCDD对具有遗传易感性的不适当炎症反应动物产后免疫不良后果的疑问。
将易患狼疮的SNF(1)小鼠在妊娠第12天暴露于0、40或80 μg/kg的TCDD,并在36周龄时检查其免疫调节作用,这些作用与狼疮病理恶化相关。
产前TCDD使成年雄性和雌性小鼠的骨髓前B细胞和大前B细胞减少,前B细胞和未成熟B细胞也减少。雄性小鼠脾脏中CD23(-) CD1(hi)和CD19(+) CD5(+) B细胞增加,雌性小鼠中B220(hi) B细胞增加,进一步表明产前TCDD对B细胞淋巴细胞生成的持续破坏。雌性小鼠经刀豆蛋白A激活的脾细胞产生的IL - 10减少,而雄性小鼠IL - 4分泌不足。80 μg/kg TCDD使两性的自身反应性CD4(+) Vβ17a(+)脾脏T细胞增加。雄性小鼠而非雌性小鼠的抗双链DNA和心磷脂自身抗体水平升高。
产前TCDD增强了易患狼疮的SNF(1)小鼠中系统性红斑狼疮进展的标志性指标,包括肾脏免疫复合物沉积、肾小球肾炎和系膜增生。因此,产前TCDD在狼疮样自身免疫性SNF(1)小鼠中引起产后免疫反应的持续调节,并加剧炎症性疾病。