Abstract
<title>Abstract</title> <p>Background Blood cadmium has been associated with depressive symptoms, but tobacco exposure is a major source of cadmium and is itself strongly related to depression. We examined the associations of blood cadmium and lead with depressive symptoms and assessed how estimates changed after accounting for smoking-related and lifestyle factors. Methods This cross-sectional study used data from 30,358 adults aged 20 years or older in the 2005–2020 pre-pandemic National Health and Nutrition Examination Survey. Depressive symptoms were defined as a Patient Health Questionnaire-9 score of at least 10. Blood cadmium and lead concentrations were natural-log transformed and standardized. Survey-weighted logistic regression was used to estimate associations across sequential covariate models. Quartile, restricted cubic spline, sensitivity, subgroup, and exploratory indirect-pathway analyses were also performed. Results The weighted prevalence of depressive symptoms was 7.81%. In the demographic- and socioeconomic-adjusted model, each 1-standard-deviation increase in log-transformed blood cadmium was associated with higher odds of depressive symptoms (odds ratio 1.258, 95% confidence interval 1.193–1.326), whereas blood lead was not (odds ratio 1.006, 95% confidence interval 0.930–1.087). Cadmium remained positively associated in the mutually adjusted lead–cadmium model (odds ratio 1.296, 95% confidence interval 1.228–1.367), and dose–response analyses were consistent with an approximately linear association. After additional adjustment for smoking and alcohol use, however, the cadmium estimate was attenuated to the null (odds ratio 1.020, 95% confidence interval 0.942–1.104); estimates also remained non-significant in models accounting for body mass index, serum cotinine, or chronic conditions. Exploratory analyses identified indirect-pathway signals involving inflammation, sleep disturbance, and nutritional factors, but these cross-sectional estimates cannot establish mediation. Conclusions Blood cadmium was associated with depressive symptoms before, but not after, adjustment for smoking-related and lifestyle factors. The findings do not support a strong association independent of tobacco-related factors and underscore the need for longitudinal studies with detailed measures of smoking and cumulative cadmium exposure.</p>