Hawkey Andrew B, Fan Rongxi, Nwachukwu Kala, Liu Shutong, Gondal Anas, Natarajan Sarabesh, Porter Jade, Marchese Melissa, Mesarick Giuliana, Stout Megan, Wells Corinne, Rezvani Amir H, Levin Edward D
Department of Biomedical Sciences, Midwestern University, Downers Grove, IL, USA; Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC, USA.
Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC, USA.
Neurotoxicol Teratol. 2025 Aug 11;111:107546. doi: 10.1016/j.ntt.2025.107546.
Neurotoxic risks in the environment come from many toxicants, which are often found together in complex mixtures. However, nearly all experimental studies evaluate one chemical at a time. Neurobehavioral effects of developmental exposure to heavy metals such as cadmium (Cd) and polycyclic aromatic hydrocarbons (PAHs) such as benzo[a]pyrene (BaP) have been well-studied, however their potential for non-additive or interactive effects are not well known. We recently reported that, in zebrafish, embryonic exposure to the PAH benzo[a]pyrene (BaP) and/or the heavy metal cadmium chloride (CdCl) led to selective sub-additive effects on behavior. The current study was performed in rats, to determine whether such interactions translate to mammals and to better account for characteristics like biological sex. In this study, we exposed female rats to BAP (0.03 mg/kg/day), the metal salt CdCl (0.3 mg/kg/day) or both via osmotic minipumps throughout gestation. Male and female offspring were assessed for bodily and reflex development, and locomotor, emotional and cognitive function. Cd treatment was associated with impaired sex differences in neonatal anogenital distance, enhanced negative geotaxis performance on PND7, reduced body weight at weaning, increased open-arm exploration in the elevated plus maze (females only), and reductions in sex differences in novel object recognition. Co-treatment with BaP attenuated those CdCl-effects on negative geotaxis and elevated plus maze. BaP was also associated with reduced metrics of food consumption in the novel environment suppressed feeding task, and with increases in errors during the initial phase of radial arm maze training (males only). As in zebrafish, persisting neurobehavioral effects are seen in rats after chronic developmental exposure to BaP and CdCl. However, these effects can differ between single-exposures and mixtures, which indicates a need for greater clarity on interactions within such mixtures.
环境中的神经毒性风险来自多种有毒物质，这些物质常常以复杂混合物的形式共同存在。然而，几乎所有的实验研究每次只评估一种化学物质。发育过程中接触重金属（如镉（Cd））和多环芳烃（PAHs）（如苯并[a]芘（BaP））的神经行为影响已得到充分研究，但其非相加或交互作用的潜力尚不清楚。我们最近报告称，在斑马鱼中，胚胎期接触PAH苯并[a]芘（BaP）和/或重金属氯化镉（CdCl）会对行为产生选择性亚相加效应。本研究在大鼠中进行，以确定这种相互作用是否适用于哺乳动物，并更好地考虑生物性别等特征。在本研究中，我们在整个妊娠期通过渗透微型泵将雌性大鼠暴露于BAP（0.03 mg/kg/天）、金属盐CdCl（0.3 mg/kg/天）或两者同时暴露。对雄性和雌性后代进行身体和反射发育以及运动、情绪和认知功能评估。镉处理与新生儿肛门生殖器距离的性别差异受损、PND7时负趋地性表现增强、断奶时体重减轻、高架十字迷宫中开放臂探索增加（仅雌性）以及新物体识别中的性别差异减少有关。与BaP共同处理可减弱CdCl对负趋地性和高架十字迷宫的影响。BaP还与新环境抑制摄食任务中食物消耗指标降低以及放射状臂迷宫训练初始阶段错误增加（仅雄性）有关。与斑马鱼一样，大鼠在慢性发育暴露于BaP和CdCl后会出现持续的神经行为影响。然而，这些影响在单次暴露和混合物之间可能有所不同，这表明需要更清楚地了解此类混合物中的相互作用。
