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Updated: May 5, 2026
Long-term Behavioral and Reproductive Consequences of Embryonic Exposure to Low-dose Toxicants
Published on: March 6, 2018
Disruption of paired-associate learning in rat offspring perinatally exposed to dioxins
Masaki Kakeyama1, Toshihiro Endo, Yan Zhang
1Laboratory of Environmental Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Bunkyo-ku, Tokyo, 113-0033, Japan.
Insights
Environmental chemical exposure, specifically dioxins like TCDD and TBDD, can impair cognitive functions in developing rats. Lower doses during gestation affected learning and increased anxiety-like behaviors in offspring.
Area of Science:
- Neuroscience
- Environmental Toxicology
- Developmental Biology
Background:
- Cognitive abnormalities in children are increasingly linked to environmental chemical exposures.
- Robust animal models are crucial for investigating the impact of these exposures on higher brain functions.
- Paired-associate learning, vital for human language acquisition, serves as a key indicator of cognitive function.
Purpose of the Study:
- To evaluate the effects of in utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 2,3,7,8-tetrabromodibenzo-p-dioxin (TBDD) on higher brain function in rat offspring.
- To assess paired-associate learning and anxiety-like behaviors using a novel flavor-location associative learning task.
- To determine if TCDD and TBDD exhibit similar effects on cognitive and emotional development.
Main Methods:
- Pregnant Long-Evans rats were administered TCDD or TBDD (0, 200, or 800 ng/kg) on gestational day 15.
- Offspring were tested in adulthood using a behavioral task assessing paired-associate learning of six unique flavor-location pairs.
- Emotional behavior was assessed by measuring latencies to enter a test arena, indicating anxiety-like behavior.
Main Results:
- Exposure to 200 ng/kg of TCDD (TCDD-200) and TBDD (TBDD-200) significantly impaired paired-associate learning in adult offspring.
- Higher doses (800 ng/kg) of TCDD and TBDD did not result in learning impairments, suggesting a nonmonotonic dose-response.
- The TCDD-200 and TBDD-200 groups exhibited significantly longer latencies to enter the test arena, indicating increased anxiety-like behavior.
Conclusions:
- Both TCDD and TBDD, at lower exposure levels, adversely affect higher brain function and emotional behavior in rat offspring.
- The effects of TCDD and its brominated congener (TBDD) on cognitive and emotional development were similar.
- This study highlights the utility of the flavor-location associative learning task for assessing chemical-induced cognitive and behavioral alterations.
Abstract:
The prevalence of cognitive abnormalities in children has partly been ascribed to environmental chemical exposure. Appropriate animal models and tools for evaluating higher brain function are required to examine this problem. A recently developed behavioral test in which rats learn six unique flavor-location pairs in a test arena was used to evaluate paired-associate learning, a hallmark of the higher cognitive function that is essential to language learning in humans. Pregnant Long-Evans rats were dosed by gavage with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 2,3,7,8-tetrabromodibenzo-p-dioxin (TBDD) at a dose of 0, 200, or 800 ng/kg (referred as Control, TCDD-200, TCDD-800, TBDD-200, or TBDD-800, hereafter) on gestational day 15, and the offspring was tested during adulthood. Paired-associate learning was found to be impaired in the TCDD-200 and TBDD-200 groups, but not in either group exposed to 800 ng/kg, the observations of which were ensured by non-cued trials. As for the emotional aspect, during habituation, the TCDD-200 and TBDD-200 groups showed significantly longer latencies to enter the test arena from a start box than the Control, TCDD-800, and TBDD-800 groups, suggesting that the TCDD-200 and TBDD-200 groups manifested anxiety-like behavior. Thus, both the chlorinated dioxin and its brominated congener affected higher brain function to a similar extent in a nearly identical manner. Use of the behavioral test that can evaluate paired-associate learning in rats demonstrated that in utero and lactational exposure to not only TCDD but also TBDD perturbed higher brain function in rat offspring in a nonmonotonic manner.
