The neuroendocrine effects of non-dioxine-like-PCBs: filling in the gap

Clearly, the neurotoxic potential of NDL-PCBs has been associated with neurobehavioral effects, including changes in motor activity, learning, memory and attention, which have been associated with neurotransmitter systems. So far, much research has been focused on presynaptic mechanisms, such as neurotransmitter levels and calcium homestasis. However, there is a lack of knowledge on mechanistic information regarding postsynaptic neurotransmitter receptors. Endocrine toxicity of NDL-PCBs involves among others androgenic and estrogenic interactions, which have been related to sex-dependent behavior and morphological changes in gonads, adrenal glands and brain. However, there is a signifcant lack of information on how individual congeners interact with steroidogenic enzymes and endocrine receptors and their mechanism of action. Therefore, the main purpose of this thesis is to gain further insight in the neurotoxic and endocrine disruptive potential of these NDL-PCBs. Chapters 2 and 3 focus on the potential neurotoxicity of NDL-PCBs and their effects on the postsynaptic human GABAA receptor. In 2005 the EFSA has identified six common NDL-PCBs which alone represent approximately 50% of all NDL-PCBs present in food. However, due to the limited number of in vivo and in vitro studies performed with NDL-PCBs, risk characterization and assessment is hampered. Further, direct and acute effects of NDL-PCBs on specific neurotransmitter receptors had not been described uptil the beginning of this thesis. Therefore, in chapter 2 the effects of six common NDL-congeners on the GABAA receptor were investigated. Further, because human exposure is not restricted to single congeners, the effects of binary mixtures of NDL-PCBs on the GABAA receptor were also studied. The limited number of congeners studied in chapter 2 impaired the identification of a SAR of NDL-PCBs on the GABAA receptor. Therefore, the set of NDL-PCBs used in chapter 3 was enlarged, including an extra DL-congener as well. The choice of the used congeners was based on their chemical and physical properties, environmental abundance and toxicological activities. Further, the binary mixtures used in this chapter aimed at assessing the effects not only on potentiation, but also on activation of the receptor. Experimental in vivo results have described sex dependent endocrine disruptive potential of NDL-PCBs. Further, the effects were apparently dependent on the time of exposure. However, many of these studies were performed with (reconstituted) mixtures and the purity of the used NDL-congeners was not always assured. Taken together, the endocrine disruptive effects seen could partially be attributed to the presence of DL-PCBs, known to interfere with the steroidogenic pathway and showing endocrine and reproductive disruptive potential. The brain, adrenals and gonads constitute an important axis in maintaining sex steroid homeostasis and regulating steroidogenesis during perinatal development and adult life. In chapter 4 the effects of perinatal exposure to two commonly found NDL-PCBs on aromatase activity on gonadal and adrenal microsomes at various life-stages were investigated. Moreover, gene expression of aromatase and sex steroid receptor expression in adult rat brain were also assessed. Traditional risk assessment of potential endocrine-disruptive pollutants, including PCBs, focus mainly on the effects of parent compounds. Still, biotransformation results in systemic exposure to PCBs and their bioactive metabolites. In chapter 5, a more mechanistic approach of the effects of twenty NDLPCBs was taken by studying aromatase activity in human placental microsomes and in the H295R cell line. In addition, the interaction of twenty NDL-PCBs with the glucocorticoid receptor (GR) was studied in a recently developed yeast-based glucocorticoid receptor assay. Because high levels of OH-PCBs and MeSO2-PCBs can also be found in human samples, these were studied in these assays as well. Taken together, the data described in this thesis show the potential neuroendocrine effects of NDL-PCBs and their metabolites. Further, perinatal PCB exposure appears to cause persistent neuroendocrine developmental effects that can be detected in adults. A summary and general discussion of the results described in this thesis are given in chapter 6.