Environmental bisphenol exposure, infant brain and behavior: Human and animal models

在子宫内，双酚A(BPA)暴露会干扰动物和人类的神经行为发育。这个 在子宫内将BPA暴露于神经行为发育的途径可能涉及在子宫内对 婴儿大脑发育，以及通过中断出生后母婴互动而产生的间接影响。父母 社交行为可能特别容易受到内分泌干扰化学物质的影响，如BPA 行为由荷尔蒙启动和社交/父母大脑的组织塑造。大多数 人类文献确定了双酚A对年龄较大的儿童的影响，很少关注生命的第一年。在啮齿动物和 灵长类动物，子宫内暴露于BPA会扰乱后代的认知和社会发育以及母体护理 通过表观遗传变化。在人类中，双酚A对婴儿大脑发育和注意力的直接影响，以及 BP引起的母婴相互作用的变化对这些影响的调制还没有得到检验。我们 因此，不知道双酚A可能通过哪些途径破坏发育。尽管双酚A已被移除 在许多消费品中，它已被结构类似物双酚-S(BPS)和双酚-f取代 (Bpf)，这可能具有类似的有害影响。这项研究将：1)检查子宫内血压与 (联合暴露)暴露与婴儿大脑功能和注意力，2)进行一项平行的啮齿动物研究 子宫内BP暴露对脑细胞和分子变化的影响，以及3)翻译一种人类方法 研究母婴相互作用用于我们的啮齿动物模型，并确定BP对这些 照看互动。在人类和啮齿动物中，我们询问是否在子宫内检测到BP之间的关联 而大脑和认知发展受到BP诱导的母婴相互作用变化的影响。在我们的 翻译法，我们在1个月和9个月大的时候招募婴儿，评估婴儿的大脑功能和注意力 在两个时间点，我们利用之前资助的母婴互动测量来测试其 缓和对这些关联的影响。在我们的平行啮齿动物模型中，我们测量了BP暴露对 子代大脑皮质基因表达、结构、注意力和母婴相互作用的质量。 影响：R01解决了我们在了解子宫内如何暴露于内分泌干扰方面的一个关键空白 化学物质会改变婴儿的大脑和认知功能。了解这些影响对于开发 筛选工具和干预对神经发育的下游影响。R01还提供 初步数据，用于该团队未来的翻译协作。未来的动物研究将 通过交叉培养实验来理清BP的直接和间接影响，人类研究将 跟随这一队列到学龄期，调查BP对神经发育的影响的神经相关性。

In utero bisphenol A (BPA) exposure disturbs neurobehavioral development in animals and in humans. The pathways linking in utero BPA exposure to neurobehavioral development likely involve direct effects in utero on infant brain development, and indirect effects via disruption of postnatal mother-infant interactions. Parental social behaviors may be especially vulnerable to endocrine-disrupting chemicals such as BPA as these behaviors are shaped by hormonal priming and by the organization of the social/parental brain. Most of the human literature identifies effects of BPA in older children, with little focus on the first year of life. In rodent and primate models, in utero exposure to BPA disrupts offspring cognitive and social development and maternal care via epigenetic changes. In humans, the direct effect of BPA on infant brain development and attention, and the modulation of these effects by BP-induced changes to mother-infant interaction, have not been examined. We thus do not know the pathways through which BPA may disrupt development. Although BPA has been removed from many consumer products, it has been replaced by structural analogs, bisphenol-s (BPS) and bisphenol-f (BPF), which may have similar detrimental effects. This study will: 1) examine associations between in utero BP (combined exposure) exposure and infant brain function and attention, 2) conduct a parallel rodent study of the effects of in utero BP exposure on cellular and molecular changes in the brain, and 3) translate a human method of studying mother-infant interaction for use in our rodent model and determine the effects of BP on these caregiving interactions. In both humans and rodents, we ask whether associations detected between in utero BP and brain and cognitive development are moderated by BP-induced change in mother-infant interaction. In our translational approach, we recruit infants at 1- and 9-months old and assess infant brain function and attention at two timepoints, and we leverage previously funded measurement of mother-infant interaction to test its moderating effects on these associations. In our parallel rodent model, we measure effects of BP exposure on offspring cortical gene expression, structure, attention and quality of mother-infant interactions. Impact: This R01 addresses a critical gap in our understanding of how in utero exposure to endocrine-disrupting chemicals alters infant brain and cognitive function. Understanding these effects is essential to developing screening tools and intervention for downstream effects on neurodevelopment. The R01 also provides preliminary data for use in future translational collaborations among this team. Future animal studies will disentangle the direct and indirect effects of BP through cross-fostering experiments, and human studies will follow this cohort into school age to investigate neural correlates of BP-induced effects on neurodevelopment.