Understanding the Relationship Between Environmental Endocrine Disrupting Chemicals, Neuropsychiatric Outcomes, and Related Biological Processes in Depression

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Environmental endocrine disrupting chemicals (EDCs) are associated with multiple adverse health effects. Early- life exposures alter neurobehavioral trajectories, with increased risk for depression and poorer cognitive functioning in childhood. However, very few studies have evaluated the effects of EDC exposure in later life despite ongoing exposure. Patients with a history of major depression (MDD) are at increased risk for neuropsychiatric symptoms such as low mood and cognitive dysfunction and this risk is further elevated in women during the menopausal and post-menopausal period. Preclinical and clinical evidence suggests that EDCs affect a number of biological variables implicated in mood and cognitive disorders, including inflammatory biomarkers, brain-derived neurotrophic factor (BDNF), and sex hormones. The proposed study seeks to better understand how EDCs affect mood and cognition in postmenopausal women with and without depression. We propose to evaluate 1) the association between EDCs and neuropsychiatric symptoms (mood and cognition) in postmenopausal women with MDD and without mood disorders (healthy controls; HC), 2) the relationship between EDCs and biological variables including inflammatory cytokines like C-reactive protein, interleukin-6, and tumor necrosis factor-α, BDNF, and sex hormones including estradiol and testosterone, and 3) whether the biological variables of interest mediate any potential association of EDCs with neuropsychiatric outcomes. We will leverage ongoing data collection of an existing study of postmenopausal women including depression rating scale scores and detailed cognitive assessment data, as well as serum cytokine, BDNF, and sex hormone levels. Urinary bisphenols and a suite of 16 phthalate metabolites will be measured in 75 MDD and 75 HC subjects. Urine will be collected at 2 timepoints (at recruitment and 1 month later), then pooled for EDC assessment. Regression and statistical methods for mixtures will be used to assess relationships between individual EDCs and their mixtures with neuropsychiatric outcomes and biomarkers. Mediation analysis will explore the direct and indirect effect of EDCs on outcome measures via the biological variables. Career development plan goals include gaining competency in the interpretation of environmental exposures and inflammatory data and in biostatistics, especially mixture methods of analysis. Training goals will be met by coursework, workshops/seminars, conferences, lab experience, readings, and mentorship. Training experiences will mostly take place at Harvard- affiliated BWH and HSPH. This project will identify emotional and cognitive effects and relevant biological effects of EDCs in a population vulnerable to neuropsychiatric symptoms. Enhanced mechanistic understanding will allow novel interventions targeting contributory biological variables, such as lifestyle changes or medications that reduce inflammation, increase BDNF, and regulate sex hormones to mitigate adverse effects of EDCs. Increased awareness of neuropsychiatric implications of EDC exposures may also guide public policy changes that regulate or reduce their omnipresence in consumer products and the environment.