Maternal dimethoxyethyl phthalate exposure enhances nicotine challenge-induced locomotor sensitization in adult male offspring rats: role of striatal dopamine D1 receptor

Early-life exposure to environmental endocrine disruptors, such as phthalates and bisphenol A, has been linked to neurobehavioral disorders, including autism spectrum disorder and attention-deficit/hyperactivity disorder (ADHD). Recent studies have also reported that individuals with ADHD exhibit higher rates of nicotine dependence than controls do. Moreover, bisphenol A has been reported to potentiate morphine- and methamphetamine-induced addictive behaviors in rodents.

Based on these findings, the present study investigated whether maternal dimethoxyethyl phthalate (DMEP) exposure influences susceptibility to locomotor sensitization induced by nicotine challenge in young adult male offpring rats. Compared with the saline control treatment, maternal exposure to DMEP did not induce locomotor hyperactivity in adult male offspring rats. However, repeated nicotine treatment induced greater development and expression of locomotor sensitization in adult male offspring rats that were maternally exposed to DMEP than in those maternally exposed to saline.

Moreover, maternal exposure to DMEP resulted in elevated dopamine (DA) levels and elevated mRNA expression of the DA D1 receptor, but not the DA D2 receptor, and c-Fos in the dorsal striatum of adult male offspring rats. Furthermore, the administration of the D1 receptor antagonist SCH23390 attenuated the enhanced locomotor hyperactivity induced by nicotine challenge following a 3-day abstinence period in adult male offspring rats maternally exposed to saline or DMEP. Interestingly, a low dose of SCH23390 significantly suppressed nicotine challenge-induced locomotor sensitization in the offspring that were maternally exposed to DMEP, but not in the offspring maternally exposed to saline.

Collectively, these findings provide novel evidence that maternal DMEP exposure increases vulnerability in adult male offspring rats to at least nicotine-induced behavioral sensitization, potentially through the upregulation of the D1 receptor in the dorsal striatum. The authors would like to thank all the research staff (Tae-Wan Kim, Ri-Na Lim, and Sun Wha Chon) at the Korea Institute of Toxicology (KIT) for providing assistance with the experiments. This research was supported by National Research Foundation of Korea (NRF) grants funded by the Korea government (MSIT) (2021R1A2C1009755 and RS-2025-00520266), a National Research Council of Science & Technology grant (CAP21025-000), and aKorea Institute of Toxicology (KS-2603-02: No. 2710110695).

Center for Convergence Toxicology Research, Division of Next-Generation Non-Clinical Research, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea Eun Young Jang, Sumin Ban, Oc-Hee Kim, Kyung Oh Jeon & Sung-Ae Hyun Department of Biochemistry, College of Natural Science, Chungnam National University, Daejeon, 34134, Republic of Korea Center for National Toxicology AI & Data, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea School of Korea Institute of Toxicology, University of Science and Technology, Daejeon, 34113, , Republic of Korea Department of Psychology and Center for Neuroscience, Brigham Young University, Provo, UT, 84602, USA Department of Neurosurgery, Brain & Spine, College of Medicine, University of South Florida, Tampa, FL, 33602, USA The authors declare no competing interests. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material.

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