Exposure to endocrine-disrupting chemicals during periods of development: The effects of phthalates on the structure of the rat medial prefrontal cortex and hippocampus and associated cognitive behaviors

Sellinger, Elli Patricia

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https://hdl.handle.net/2142/120244 Copy

Description

Title

Exposure to endocrine-disrupting chemicals during periods of development: The effects of phthalates on the structure of the rat medial prefrontal cortex and hippocampus and associated cognitive behaviors

Author(s)

Sellinger, Elli Patricia

Issue Date

2023-04-12

Director of Research (if dissertation) or Advisor (if thesis)

Juraska, Janice M

Doctoral Committee Chair(s)

Juraska, Janice M

Committee Member(s)

• Raetzman, Lori
• Liang, Nu-Chu
• Hinman, James

Department of Study

Neuroscience Program

Discipline

Neuroscience

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• DEHP
• DEP
• DBP
• DiNP
• DiBP
• BBP
• EDC
• mPFC
• dorsal hippocampus
• ventral hippocampus
• adolescence
• perinatal

Abstract

The literature examining humans suggests a link between developmental phthalate exposure and adverse neurodevelopmental outcomes (Ejaredar et al., 2015; Engel et al., 2021), however the causative nature of this relationship necessitates the use of animal models. Unfortunately, a large majority of the existing literature studying the effects of phthalates on neurodevelopment in rodents employs high doses of single phthalates, demonstrating the potential for phthalates to exert severe effects on the brain but failing to the acknowledge this exposure is not representative of that seen in humans. This dissertation therefore aims to add clarity to the effects of phthalates on the development of two cognitive regions, the medial prefrontal cortex (mPFC) and the hippocampus, using a mixture and doses relevant to human exposure. Phthalates are a class of endocrine-disrupting chemicals used to add flexibility to PVC plastics common in food packaging and food processing equipment as well as in medical equipment (IV tubing), to preserve fragrance in personal care products, and improve consistency in cosmetics. One of phthalates’ many mechanisms of action is disrupted gonadal hormone signaling, so the negative effects of phthalates on the reproductive system have been well studied (Mariana et al., 2016). However, gonadal hormones are also implicated in processes of neurodevelopment occurring during the perinatal period (Forger, 2006; Nuñez et al., 2000) and during adolescence (Koss et al., 2015, Drzewiecki et al., 2016), therefore providing potential for disruption by phthalate exposure. Chapter 1 first provides background on phthalates and potential mechanisms of action in the body. Then it reviews correlational studies performed in humans as well as studies performed in rodent models that show the effects developmental phthalate exposure can have on brain structure and related cognitive functions. Furthermore, the development, structure, and function of the two regions of interest, the hippocampus and the mPFC, are described to provide context for how exposure to phthalates could result in lasting structural and functional changes to these areas. Chapter 2 focuses on effects of phthalate exposure during the adolescent period on the anatomy of the mPFC and its related cognitive behaviors. We show adolescent phthalate exposure does not alter adult gray matter volume or performance on a battery of tasks: (1) attentional set shift, an mPFC-dependent task assessing cognitive flexibility, (2) prepulse inhibition measuring sensorimotor gating, and (3) the elevated plus maze reflecting anxiety-like behavior. Therefore, these experiments suggest the adolescent mPFC is relatively resistant to phthalate action. Chapter 3 returns to a focus on perinatal phthalate exposure, examining the mechanism behind the lasting decrease in neuron number previously observed in the mPFC after perinatal exposure (Kougias et al., 2018b). We show phthalates increase levels of cell death prenatally on embryonic day (E)18 as well as on postnatal day (P)10. Furthermore, embryonic BrdU labeling quantified on P5 suggests a potential decrease in proliferation, however it is possible this finding is simply the result of decreased cell survival. Therefore, these experiments demonstrate the capacity for a low dose mixture of phthalates to alter levels of developmental cell death and possibly proliferation in the mPFC. Chapter 4 explores the effects of perinatal phthalate exposure on a second brain region, the hippocampus. The immediate effects of exposure on developmental cell death are examined as well as the lasting effects on the number of neurons in the adult hippocampus and associated cognitive behaviors using the Morris water maze and a social memory task. We first establish basal patterns of cell death in dorsal and ventral CA fields revealing apoptosis increases in CA3 on P2 and a rise in CA1 follows on P5 in both sexes. Surprisingly, the addition of phthalate exposure leads to a slight reduction in apoptosis in dorsal and ventral CA1 at several postnatal ages (P2, P5, and P10), again largely in both sexes. One sex-specific effect occurs on P10 where cell death is reduced only in female ventral CA1. However, these subtly altered patterns of cell death did not lead to a lasting change in adult hippocampal neuron number or alter hippocampal-dependent spatial or social memory. Therefore, these studies suggest that while hippocampal development may be altered by phthalate exposure, this structure has the capacity to compensate for these small effects. Together, these studies add to our understanding of how exposure to phthalates impacts the developing brain using a mixture and doses relevant to humans. Our examination of exposure during the adolescent period and lack of effects suggests the perinatal period is most susceptible to phthalate action. Furthermore, our comparison of phthalate-induced cell death in two distinct brain regions demonstrates the effects of phthalates on the developing brain are not globally uniform. Moreover, the lack of robust sex-specific effects of phthalate exposure suggests alternative mechanisms of action rather than gonadal hormone signaling should be investigated. With the widespread use of phthalates across multiple industries and the lack of a cost-effective, non-EDC alternative, persistent exposure to these compounds will likely continue. To better understand the risks of exposure and to inform policy around the continued use of phthalates in consumer products, additional research on how these toxicants impact the developing brain using human relevant mixtures and doses is imperative.

Graduation Semester

2023-05

Type of Resource

Thesis

Copyright and License Information

Copyright 2023 Elli Sellinger

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