OBJECTIVE: This study aimed to explore the associations of tobacco smoke exposure (TSE) and heavy metal exposure on sex hormones and the joint effects between them in adult males. METHODS: The study used data of 2244 adult males from the National Health and Nutrition Examination Survey (NHANES, 2013-2016). Weighted linear regression models were used to calculate their beta (β) coefficients and corresponding confidence interval (95% CI), which assessed the joint effects of TSE and heavy metals on sex hormones. RESULTS: Sex hormone-binding globulin (SHBG) showed a positive association with increased per standard deviation (SD) for cotinine (β=0.024 [0.004, 0.043]
P<
0.001), lead (β=0.021 [0.002, 0.039]
P=0.028), and cadmium (β=0.034 [0.015, 0.053]
P<
0.001). Manganese was positively associated with estradiol (E2) (β=0.025 [0.009, 0.042]
P=0.002). The subjects with higher cadmium levels were more likely to have higher total testosterone (TT) (β=0.042 [0.023, 0.062]
P<
0.001). TSE and lead exerted synergistic effects on TT (p for interaction = 0.015) and E2 (p for interaction = 0.009), as also did TSE and cadmium on SHBG (p for interaction = 0.037). Compared with the reference group, TSE participants who were exposed to high concentrations of lead, cadmium, mercury, and manganese had significantly elevated TT levels, but these high levels presented no significant association with E2 levels. A significantly higher level of SHBG among TSE participants was detected in high concentrations for lead, cadmium, and mercury. CONCLUSION: TSE exacerbated sex hormone imbalances when combined with high levels of metal exposure. Smoking cessation is crucial, especially in the case of high levels of occupational exposure to heavy metals.