Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA.
Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, MI, USA.
Sci Total Environ. 2023 Nov 20;900:165674. doi: 10.1016/j.scitotenv.2023.165674. Epub 2023 Jul 25.
Gestational exposure to environmental chemicals (ECs) is associated with adverse, sex-specific offspring health effects of global concern. As the maternal steroid, cytokine and oxidative stress milieus can have critical effects on pregnancy outcomes and the programming of diseases in offspring, it is important to study the impact of real-life EC exposure, i.e., chronic low levels of mixtures of ECs on these milieus. Sheep exposed to biosolids, derived from human waste, is an impactful model representing the ECs humans are exposed to in real-life. Offspring of sheep grazed on biosolids-treated pasture are characterized by reproductive and metabolic disruptions.
To determine if biosolids exposure disrupts the maternal steroid, cytokine and oxidative stress milieus, in a fetal sex-specific manner.
Ewes were maintained before mating and through gestation on pastures fertilized with biosolids (BTP), or inorganic fertilizer (Control). From maternal plasma collected mid-gestation, 19 steroids, 14 cytokines, 6 oxidative stress markers were quantified. Unpaired t-test and ANOVA were used to test for differences between control and BTP groups (n = 15/group) and between groups based on fetal sex, respectively. Correlation between the different markers was assessed by Spearman correlation.
Concentrations of the mineralocorticoids - deoxycorticosterone, corticosterone, the glucocorticoids - deoxycortisol, cortisol, cortisone, the sex steroids - androstenedione, dehydroepiandrosterone, 16-OH-progesterone and reactive oxygen metabolites were higher in the BTP ewes compared to Controls, while the proinflammatory cytokines IL-1β and IL-17A and anti-inflammatory IL-36RA were decreased in the BTP group. BTP ewes with a female fetus had lower levels of IP-10.
These findings suggest that pre-conceptional and gestational exposure to ECs in biosolids increases steroids, reactive oxygen metabolites and disrupts cytokines in maternal circulation, likely contributors to the aberrant phenotypic outcomes seen in offspring of BTP sheep - a translationally relevant precocial model.
环境化学物质（ECs）的妊娠期暴露与具有全球关注的、特定性别相关的后代健康影响有关。由于母体类固醇、细胞因子和氧化应激环境对妊娠结局和后代疾病的发生具有关键影响，因此研究真实 EC 暴露（即慢性低水平的 EC 混合物）对这些环境的影响非常重要。接触生物固体（来源于人类废物）的绵羊是一种具有影响力的模型，代表了人类在现实生活中接触的 EC。接触生物固体处理过的牧场的绵羊后代表现出生殖和代谢紊乱。
以胎儿性别特异性的方式确定生物固体暴露是否会破坏母体类固醇、细胞因子和氧化应激环境。
在交配前和妊娠期间，将母羊饲养在生物固体（BTP）或无机肥料（对照）施肥的牧场上。从中期母体血浆中提取 19 种类固醇、14 种细胞因子和 6 种氧化应激标志物进行定量分析。分别使用独立样本 t 检验和方差分析来检测对照组和 BTP 组之间（n=15/组）以及基于胎儿性别的组间差异。使用 Spearman 相关性评估不同标志物之间的相关性。
与对照组相比，BTP 组的矿物质皮质激素-脱氧皮质酮、皮质酮、糖皮质激素-脱氧皮质醇、皮质醇、可的松、性激素-雄烯二酮、脱氢表雄酮、16-OH-孕酮和活性氧代谢物浓度更高，而促炎细胞因子 IL-1β和 IL-17A 以及抗炎细胞因子 IL-36RA 浓度在 BTP 组中降低。BTP 组中具有雌性胎儿的母羊 IP-10 水平较低。
这些发现表明，生物固体中的 EC 预受孕和妊娠期暴露增加了类固醇、活性氧代谢物，并破坏了母体循环中的细胞因子，这可能是 BTP 绵羊后代异常表型结果的原因之一——这是一个具有转化意义的早产模型。
