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Title:Effects of perinatal exposure to a mixture of phthalates and a maternal high-fat diet on the neurodevelopment of male and female rats
Author(s):Kougias, Daniel G.
Director of Research:Juraska, Janice M.
Doctoral Committee Chair(s):Juraska, Janice M.
Doctoral Committee Member(s):Gulley, Joshua M.; Raetzman, Lori T.; Schantz, Susan L.
Department / Program:Neuroscience Program
Degree Granting Institution:University of Illinois at Urbana-Champaign
endocrine disruptor
endocrine-disrupting chemicals
sex differences
prefrontal cortex
Abstract:Humans are ubiquitously exposed to many phthalates, a class of endocrine-disrupting chemicals commonly used as plasticizers in a variety of consumer products. Since diet is the predominant source of exposure to many phthalates due to environmental contamination and fatty foods possess a higher concentration of phthalates, it is important to study them together. Furthermore, both exposure to phthalates and a high-fat diet (HFD) are common and can separately cause oxidative stress and inflammation. As the prenatal period is crucial for brain development and is particularly prone to environmental insult, the purpose of this dissertation is to examine the neurodevelopmental effects of prenatal exposure to phthalates in conjunction with a maternal HFD. In particular, the set of studies within the following chapters uses a rat model of human prenatal exposure to investigate the developmental, behavioral, and neural effects of an environmentally relevant mixture of phthalates (0, 200, or 1000 mg/kg/d) and a maternal HFD, with a specific emphasis on the medial prefrontal cortex (mPFC). The mPFC is of particular interest given its involvement in executive function and social behavior, as well as its implication in the pathology of many neuropsychiatric disorders, some of which have been positively associated with prenatal phthalate exposure (Ejaredar et al., 2015) and maternal obesity (Sanchez et al., 2017). Given that phthalates and a maternal HFD are known to separately result in similar adverse neurodevelopmental outcomes, we hypothesized that the combination may have additive effects possibly mediated via common effects on inflammation and oxidative stress. What was found, however, was that perinatal exposure to phthalates and a HFD resulted in independent effects that rarely interacted. In the set of studies here, we add to the existing rodent literature, and support the human literature, in demonstrating that perinatal exposure to an environmentally relevant mixture of phthalates results in adverse neurodevelopmental outcomes that are evident in social behaviors, startle reactivity, cognitive flexibility, and the neuroanatomy of the mPFC in both males and females. Perinatal exposure to phthalates resulted in a decrease in the total number of neurons and synapses, as well as size, of the mPFC in both adult males and females. Since there were no effects of phthalate exposure on the number of synapses per neuron in the mPFC, this suggests that neuron loss, rather than synapses per se, may underlie the phthalate-induced decrease in the total number of synapses within the mPFC. These neurotoxic effects on the mPFC as a result of phthalate exposure also appear to be immediate considering that there was a lack of consistent effects in oxidative stress markers and gene expression within the mPFC at both early and late timepoints. Here, we also demonstrate that although a HFD increased maternal caloric intake and gestational weight gain, as well as maternal care and pup prepubertal bodyweights that persisted into adulthood in males, a HFD did not have many, and certainly not robust, effects on neurodevelopment. In fact, the only salient effect that a HFD had was limited to females on cognitive flexibility, such that an early perinatal HFD appeared beneficial to cognitive flexibility in females. There were no significant effects of a HFD on the neuroanatomy of the mPFC. Overall, this study demonstrates that phthalates and a maternal HFD rarely interact, but can have separate lasting effects on behavior. Importantly, phthalates appeared to have a greater influence on adult behaviors than a HFD and, unlike a HFD, affected the neuroanatomical outcome of the adult mPFC. More research is needed to identify the types of neurons and synapses that are affected and to elucidate the mechanistic action of an environmentally relevant mixture of phthalates.
Issue Date:2018-06-25
Rights Information:Copyright 2018 Daniel Kougias
Date Available in IDEALS:2018-09-27
Date Deposited:2018-08

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