Our research was based on 49338 participants aged ≥ 3 years in NHANES, 2001–2014. We found that serum cotinine presented a positive association with 25(OH)D concentrations in 3–11 years and 12–19 years old subgroups, whereas a negative relation was shown in 20–59 years and ≥ 60 years old subgroups. No significant relationships were found between tobacco smoke exposure and VD status for children aged 3–11 years. Among active smokers aged 12–19 years, protective effects of tobacco smoke exposure were observed on VD deficiency as well as inadequacy. Both active and passive smoking were significantly associated with enhanced risk of VD deficiency in 20–59 years and ≥ 60 years subgroups. Moreover, active smokers in 20–59 years and ≥ 60 years old subgroups also had increased risk of VD inadequacy. After stratifying by gender, most of the above-mentioned effects persisted for both genders and were more pronounced in female participants. Our analyses indicated that there was somewhat age- and gender- difference for the effects of tobacco smoke exposure on VD levels. Our results also provided some evidence concerning impacts of tobacco smoke exposure on VD intoxication, which was rarely investigated in previous studies of the same content.
Our findings for relationship between tobacco smoke exposure and serum VD concentrations were partly supported by previous epidemiological studies. A Norwegian study on 205 participants aged ≥ 29 years found that serum 25(OH)D levels were significantly lower in smokers than nonsmokers (Jorde 2005). Results from 293 American females aged 18–45 years demonstrated significant decrease in serum 25-hydroxy-vitamin D3 (25-OHD3) in both active and passive smokers (Soldin 2011). A study of 181 Greece males aged 20–50 found that 25(OH)D was significantly lower in smokers compared to nonsmokers (Kassi 2015). In a cross-sectional study examining the association of smoking status with VD in 612 Chinese males aged 50 years and older, smokers also presented lower serum VD levels than nonsmokers (Jiang 2016). Contrary to our positive relations found for tobacco smoke exposure with 25(OH)D concentrations in young participants aged 3–11 years and 12–19 years subgroups, a cross-sectional study carried out in Italy reported that passive smoking exposure in 152 children aged 5–15 years had lower levels of 25(OH)D (Chinellato 2018). A Sweden cohort study based on 1068 males aged 18–20 years also indicated adverse effects of smoking on 25(OH)D levels (Lorentzon 2006). Whereas a non-significantly positive relation between smoking exposure and 25(OH)D was shown for pregnant women in an Iranian historical cohort (Banihosseini 2013).
Evidence on the association between tobacco smoke exposure and VD status was rather limited, and there were no researches to date that estimated their relationship in children and adolescents. Kassi et al. proved that young male smokers (20–29 years) had increased risk of VD deficiency (Kassi 2015). An increased risk of VD inadequacy was also detected among Spanish smokers aged 18–84 years (Cutillas-Marco 2012). The NHANES 2001–2006 analyses demonstrated that American female active smokers aged ≥ 18 years had higher prevalence of VD deficiency and inadequacy (Manavi 2015). Although these epidemiological studies were limited to adults, their findings supported our results that tobacco smoke exposure, including active and passive smoking, was associated with increased risk of VD deficiency and inadequacy. It is noteworthy that the associations for smoke exposure with VD status were significant for participants with different races and BMI categories, indicating the adverse effects of exposure were stable.
The mechanism behind the disrupting effects of tobacco smoke on VD are unclear. On the ground of the foregoing experimental and epidemiological evidence, possible mechanisms for tobacco smoke exposure to interfere with VD were recently summarized as several highly likely pathways (Mousavi 2019). First of all, smoking could induce skin aging, and smoking-derived aging may disturb the cutaneous production of VD. Second, dysfunctional VD-parathyroid hormones (PTH) axis due to tobacco smoke exposure could result in disruption of the VD metabolism. In addition, it appears that tobacco smoke is associated with dysregulation of enzymes genes related to the metabolism of VD. Another possible pathway is renal tubular dysfunction caused by tobacco smoke exposure. Heavy metals contained in tobacco may accumulate in kidneys, inhibiting VD activation through impairing kidney function. Besides, it is also hypothesized that tobacco smoke could depress intake of VD due to changed dietary taste. Although the exact explanation related to age difference is unknown, we assume that the observed protective effects of tobacco smoke exposure on VD levels in young people in our study might due to the very small numbers of exposed subjects. Nonetheless, further investigation is warranted to clearly ascertain mechanisms responsible for the reported smoking-VD associations as well as age- and gender- differences.
Our study has multiple strengths. First, our study used a nationally representative sample with a large sample size, which allowed for exploring age- and gender-difference in the associations between tobacco smoke exposure and VD levels as well as potential modifying effects of several important factors. Second, the study provided important evidence for long-term trends in tobacco smoke exposure over a 14-year period. Of note, smoking rates were consistently high over time, especially for active smoking among male adults and passive smoking among children. Third, our study was the first to investigate effects of tobacco smoke exposure on VD intoxication, giving more clues on the disruptive role of tobacco smoke.
Our results, however, should be interpreted with caution due to following limitations. First, given the cross-sectional nature of this study, no causal inference could be derived. Future evidence from prospective study design is warranted. Second, cotinine has a short half-life, and the measurement was based on a single spot serum sample. Therefore, the indicators detected could only represent a short-term level and the variation of individuals might be overlooked. Second, the lack of data on sun exposure such as season and latitude, and dietary intake of VD in NHANES 2001–2006 hindered us from elaborating the possible biological mechanisms. However, after our further adjustment for dietary VD intake for participants with full dietary data in NHANES 2007–2014, significant associations between tobacco smoke and VD deficiency persisted. Third, although stratified analyses by age, gender, ethnicity/race and BMI would help identify susceptible population, the multiple testing may also increase the chance of false positive findings. Thus, the current results from stratified analyses were exploratory.
In conclusion, serum cotinine was significantly and inversely associated with 25(OH)D in adult participants. Tobacco smoke exposure, including both active and passive smoking exposure, was associated with increased risk of VD deficiency in adults. Moreover, active smoking of adults was additionally related to increased risk of VD inadequacy. These associations showed somewhat gender difference, with consistent and stronger associations observed in female adults. In contrast, the effect of tobacco smoke exposure in children and adolescents aged 3–19 years on VD levels were mostly protective or non-significant. More researches are needed to verify our results.