Effects of cross-fostering and developmental exposure to mixtures of environmental contaminants on hepatic gene expression in prepubertal 21 days old and adult male Sprague-Dawley rats VI.

The notion that adverse health effects produced by exposure to environmental contaminants (EC) may be modulated by the presence of non-chemical stressors is gaining attention. Previously, our lab demonstrated that cross-fostering (adoption of a litter at birth) acted as a non-chemical stressor that amplified the influence of developmental exposure to EC on the glucocorticoid stress-response in adult rats. Using liver from the same rats, the aim of the current study was to investigate whether cross-fostering might also modulate EC-induced alterations in hepatic gene expression profiles. During pregnancy and nursing, Sprague-Dawley dams were fed cookies laced with corn oil (control, C) or a chemical mixture (M) composed of polychlorinated biphenyls (PCB), organochlorine pesticides (OCP), and methylmercury (MeHg), at 1 mg/kg/day. This mixture simulated the contaminant profile reported in maternal human blood. At birth, some control and M treated litters were crossfostered to form two additional groups with different biological/nursing mothers (CC and MM). The hepatic transcriptome was analyzed by DNA microarray in male offspring at postnatal days 21 and 78–86. Mixture exposure altered the expression of detoxification and energy metabolism genes in both age groups, but with different sets of genes affected at day 21 and 78–86. Cross-fostering modulated the effects of M on gene expression pattern (MM vs M), as well as expression of energy metabolism genes between control groups (CC vs C). In conclusion, while describing short- and long-term effects of developmental exposure to EC on hepatic transcriptomes, these cross-fostering results further support the consideration of non-chemical stressors in EC risk assessments.环境污染物（EC）暴露所诱发的不良健康效应可受非化学应激源调控这一学术观点，正日益受到学界关注。此前，本实验室已证实，交叉抚育（cross-fostering，即幼崽出生时的换窝寄养）作为一类非化学应激源，可放大发育阶段暴露于EC对成年大鼠糖皮质激素应激反应的影响。本研究使用该批大鼠的肝脏样本，旨在探究交叉抚育是否同样可调控EC诱导的肝脏基因表达谱改变。在妊娠与哺乳阶段，斯普拉格-道利（Sprague-Dawley, SD）母鼠被喂食添加了玉米油（对照组，C）或由多氯联苯（polychlorinated biphenyls, PCB）、有机氯农药（organochlorine pesticides, OCP）及甲基汞（methylmercury, MeHg）组成的化学混合物（M）的饼干，给药剂量为1 mg/kg/天。该混合物模拟了人类母体血液中检出的污染物谱型。幼崽出生时，部分对照组与M暴露组的幼崽窝群接受交叉抚育，由此形成两个新增组别：CC组与MM组，两组幼崽的亲生母鼠与哺乳母鼠均不相同。于出生后第21天及第78~86天，采用DNA微阵列技术对雄性后代的肝脏转录组进行分析。化学混合物暴露在两个年龄组中均改变了解毒与能量代谢相关基因的表达，但第21天与第78~86天受影响的基因集合存在差异。交叉抚育可调控M暴露对基因表达模式的影响（MM组 vs M组），同时也可调控对照组间能量代谢相关基因的表达水平（CC组 vs C组）。综上，本研究在阐明发育阶段暴露于EC对肝脏转录组的短期与长期影响的同时，上述交叉抚育相关结果进一步支持在EC风险评估中需纳入非化学应激源的考量。