Evaluation of gadolinium-based contrast agents in pregnant CD-1 mice and subsequent in utero exposure of the developing offspring, including behavioral evaluations

IF 1.6 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research Pub Date : 2023-12-29 DOI:10.1002/bdr2.2291

Elise M. Lewis, Simona Bussi, Nathalie Fretellier, Guenther Clemens, Paul Jones, Fabio Tedoldi, Phillipe Bourrinet, Oliver Czupalla, Ella Hirani, Alan M. Hoberman

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Abstract

Introduction

The offspring of CD-1 mice exposed during pregnancy to one of seven gadolinium-based contrast agents (GBCAs) were evaluated for potential effects on postnatal development and behavior. The GBCAs, comprising four linear (gadopentetate dimeglumine, gadodiamide, gadobenate dimeglumine, and gadoxetate disodium) and three macrocyclic (gadoterate meglumine, gadoteridol, and gadobutrol), were administered via intravenous injection once daily from Gestation Day 6 through 17 following confirmed mating (Day 0) at doses of at least twice the human equivalent recommended clinical dose (i.e., 0.63 mmol Gd/kg for gadoxetate disodium and 2.5 mmol Gd/kg for the other GBCAs). All dams were allowed to deliver naturally. F0 generation females were monitored for maternal toxicity and gadolinium (Gd) levels in blood and brain. Offspring were evaluated for Gd levels in blood and brain at birth and on Day 70 postpartum. F1 generation mice were evaluated for survival and growth preweaning. Selected pups/litter were evaluated postweaning for sexual maturation, growth, and behavior. Gd was quantifiable in the brain of the F1 offspring on PND 1, with levels declining over time. There was no long-term effect of any GBCA on the growth and development of any offspring. There was no impact on neurodevelopment, as assessed by brain histology and validated neurobehavioral tests, including a battery of functional observational tests, motor activity, and learning and memory as evaluated in the Morris water maze.

Conclusion

At the end of the postweaning period, the highest dose tested was considered the no-observable-adverse-effect level (NOAEL) in the F0 and F1 offspring for all tested GBCAs.

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在怀孕的 CD-1 小鼠体内评估钆基造影剂，以及发育中的后代随后在子宫内的暴露情况，包括行为评估。

简介：研究人员对怀孕期间暴露于七种钆基造影剂（GBCA）之一的 CD-1 小鼠的后代进行了评估，以确定其对出生后的发育和行为可能产生的影响。这些钆基造影剂包括四种线性造影剂（钆喷酸二葡胺、钆二酰胺、钆喷酸二葡胺和钆喷酸二钠）和三种大环造影剂（钆喷酸甲葡胺、钆特罗和钆布醇），从妊娠第 6 天到确定交配后的第 17 天（第 0 天），每天通过静脉注射给药一次，剂量至少为人体等效临床推荐剂量的两倍（即 0.63 mmol Gd/kg）、钆西他酯钠为 0.63 mmol Gd/kg，其他 GBCAs 为 2.5 mmol Gd/kg）。所有母鼠均可自然分娩。对 F0 代雌性动物进行母体毒性以及血液和大脑中钆 (Gd) 含量的监测。对出生时和产后第 70 天的后代进行血液和大脑中 Gd 含量的评估。对 F1 代小鼠断奶前的存活率和生长情况进行评估。断奶后，对每窝选定的幼鼠进行性成熟、生长和行为评估。在断奶后第 1 天，F1 代小鼠大脑中的钆可被量化，其含量随时间推移而下降。任何 GBCA 对任何后代的生长和发育都没有长期影响。通过脑组织学和有效的神经行为测试（包括一系列功能观察测试、运动活动以及在莫里斯水迷宫中评估的学习和记忆）评估，对神经发育没有影响：结论：在断奶期结束时，对于所有测试的 GBCAs，测试的最高剂量被认为是 F0 和 F1 后代的无观测不良效应水平 (NOAEL)。

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来源期刊

Birth Defects Research Medicine-Embryology

CiteScore

3.60

自引率

9.50%

发文量

153

期刊介绍： The journal Birth Defects Research publishes original research and reviews in areas related to the etiology of adverse developmental and reproductive outcome. In particular the journal is devoted to the publication of original scientific research that contributes to the understanding of the biology of embryonic development and the prenatal causative factors and mechanisms leading to adverse pregnancy outcomes, namely structural and functional birth defects, pregnancy loss, postnatal functional defects in the human population, and to the identification of prenatal factors and biological mechanisms that reduce these risks. Adverse reproductive and developmental outcomes may have genetic, environmental, nutritional or epigenetic causes. Accordingly, the journal Birth Defects Research takes an integrated, multidisciplinary approach in its organization and publication strategy. The journal Birth Defects Research contains separate sections for clinical and molecular teratology, developmental and reproductive toxicology, and reviews in developmental biology to acknowledge and accommodate the integrative nature of research in this field. Each section has a dedicated editor who is a leader in his/her field and who has full editorial authority in his/her area.