Effects of the abdominal fat distribution on the relationship between exposure to air pollutants and thyroid hormones among Korean adult males

Ambient air pollution contains known human carcinogens and is a problem worldwide, and has recently become a major public concern in Korea [1]. A report from the Organization for Economic Cooperation and Development (OECD) documented that outdoor air pollution in South Korea was estimated at 359 premature deaths per million individuals in 2010. If this situation continues, it will rise to more than 1100 per million individuals by 2060 [2]. Most premature deaths related to air pollution were linked to cardiovascular diseases, including stroke and myocardial infarction [3, 4].

In recent years, emerging evidence has shown the harmful effects of ambient air pollution on thyroid hormone levels [5‐9]. Experimental findings have shown how their toxic effects on environmental chemicals affect thyroid hormone levels [10, 11]. A more recent study has suggested that obese status mediates the association between ambient air pollution and thyroid function [1]. Although the mechanisms underlying this relationship are not understood completely, several possible hypotheses have been proposed. Obese status, especially abdominal obesity, is linked to the thyroid functions related to oxidation of fatty acids, lipid metabolism, and so on [12, 13]. Abdominal fat distribution, as measured by the subcutaneous and visceral fat area, plays a role in the high risk of diseases, including metabolic diseases, cardiovascular diseases, and hypertension [14, 15].

It is essential to understand the role of regional abdominal fat traits to understand these associations and mechanisms more fully. Excessive visceral adipose tissue (VAT) may contribute to elevated oxidative stress or oxidative damage [16, 17]. VAT secretes large amounts of cytokines that induce inflammation, including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), compared to subcutaneous fat [18, 19]. In fact, a previous study suggested an increase in VAT as the best predictor of thyrotropin (TSH) in obesity [20]. By contrast, subcutaneous fat may affect the change of thyroid hormone in specific tissue [21]. The thyroid hormone receptor is also more activated in subcutaneous adipose tissue (SAT) than in VAT [22].

In this context, we reasoned that abdominal fat may mediate the relationship between air pollution and thyroid hormone and that this may be reflected in differences according to adiposity traits. However, previous studies of the effects of obesity on the relationship between environmental pollutants and thyroid hormones have mostly used body mass index (BMI) as a proxy variable for obesity [1, 23]. This indirect indicator of obesity cannot accurately distinguish certain depots of abdominal fat. Therefore, the precise estimation of fat mass using computed tomography (CT) is essential to examine these potential associations further. To our knowledge, no studies have evaluated this hypothesis. In this study, we assessed the relationship of exposure to air pollutants and thyroid hormone in Korean adults and whether these relationships are mediated by abdominal fat type.

We assessed the associations of exposure to air pollution and thyroid hormones, including TSH and FT₄ concentration, in a Korean population and whether these relations are modified by VAT and SAT areas. We found that persistent exposure to air pollution was significantly related to increased TSH and decreased FT₄ concentrations. In the stratified analyses according to abdominal adiposity traits, PM₁₀, NO₂, and CO exposure showed a stronger association with TSH and FT₄ concentrations in the subjects with high adiposity. We identified the significant effects of PM₁₀ and CO exposure on thyroid function in all adiposity groups, as measured by WC, VAT and SAT areas, and VSR. Among the abdominal fat-related traits, the impact of air pollution exposure on the thyroid hormone level was the strongest for VSR in the subjects with high adiposity. Our findings suggest that people with high adiposity may be more likely to develop disturbances in thyroid hormones caused by air pollution, especially PM₁₀ and CO.

Epidemiological researches have shown associations between exposure to air pollutants and thyroid hormone [5, 6, 8, 9, 26], but most of these studies have shown limited results in pregnant women [5, 6, 9]. A study of children across southern California found that prenatal PM exposure was significantly associated with increased newborn thyroxine concentration [6]. Two epidemiological studies have reported an inverse relationship between PM_2.5 and NO₂ and FT₄ level during pregnancy, although the relationship with TSH level was not significant [5, 9]. A recent cross-sectional, population-based study in China reported that a 10 μg/m³ increase in PM_2.5 exposure decreased 0.12 pmol/L in FT₄ concentration [26]. Another study reported that exposure to each of the air pollutants including PM_2.5, PM₁₀, NO₂, and SO₂ was significantly and linearly associated with the risk of thyroid nodules in Chinese adults [8]. We found that FT₄ concentration decreased and TSH concentration increased with increasing exposure to air pollutants. Our results were robust even after stratifying according to abdominal adiposity traits. However, these associations require confirmation by prospective cohort studies.

Obesity, especially abdominal adiposity, is closely related to thyroid hormone levels [13]. A recent study of the association between thyroid function and distribution of abdominal adiposity suggests that SAT is independently and positively associated with elevated triiodothyronine (FT₃) concentration in a China population (male: OR = 0.183, 95% CI = 0.094 to 0.272, and female: OR = 0.089, 95% CI = 0.007–0.171) [22]. Another study also identified the positive association between abdominal subcutaneous fat and TSH or FT₃ level [27]. In contrast, a cross-sectional study reported that the excessive adipose tissue, particularly VAT, plays the crucial role in thyroid dysfunction [20]. In our study, both VAT and SAT are associated with a decrease of FT₄ concentration. These different results may be partially explained by several factors, such as study design and population.

With regard to modifying the effect of obese status on the association between exposure to air pollutants and thyroid function, our research team in 2020 provided the first clue that air pollution, including NO₂ and CO, is strongly linked to thyroid function in people with overweight or obesity [1]. However, it was only a result of showing the modifying effects of overall obesity defined by BMI. To date, to our knowledge, no studies have evaluated the relationship between exposure to ambient air pollution and thyroid functions, considering the abdominal fat distribution in the general population. We found for the first time that the relations between air pollution exposure and thyroid functions were more strongly associated in the subjects with high adiposity, as defined by high VAT, SAT, and VSR areas.

The pathophysiological mechanism linking air pollution, abdominal fat level, and thyroid function is unclear. However, possible hypotheses involving the adipocyte have been proposed. The oxidative stress reaction is the most plausible mechanism. Thyroid hormones regulate the antioxidant system via the promotion of oxidative stress and reactive oxygen species [28, 29]. Both type of hypothyroidism and hyperthyroidism have been shown to be related to oxidative damage to cell structures [28]. The toxic effect of air pollutant exposure also leads to the production of other reactive oxygen species and oxidative injury [30]. Similarly, abdominal fat, particularly the visceral fat accumulation, is responsible for activation of oxidative stress or oxidative injury [18]. In addition, inflammatory response can be a plausible mechanism. Systemic inflammation through cytokine changes induces thyroid dysfunction [28]. Obesity is related to an increased production of cytokines for the pro-inflammatory response (e.g., leptin, TNF-α, and IL-6) and a decreased secretion of adipokines that protect inflammatory response (e.g., adiponectin and IL-10). Such inflammatory cytokines are mainly secreted from visceral adipocytes [18, 19]. Besides, exposure to air pollution is implicated in systemic inflammation [31]. Therefore, our results stratified by VAT or VSR may be interpreted by the synergistic effects of exposure to air pollution and abdominal fat on the oxidative stress or inflammation. However, additional studies are needed to better understand the clear mechanisms.

The strength of our study is the observation, for the first time, that the relationship between air pollution exposure and thyroid hormone is stronger in people with high adiposity, as indicated by WC, VAT and SAT areas, and VSR. Our study has some limitations. First, this study is a cross-sectional type, which cannot be used to identify a causal relation between exposure to air pollutant, abdominal fat distribution, and thyroid hormone. Second, our study did not conduct analysis of possible sex differences in abdominal adiposity distribution because of insufficient data on women. Health outcomes caused by air pollution or obesity may differ between two sexes due to differences in patterns of physical activity, sex hormone levels, occupational features, and the way of life, as well as differences in adiposity distribution. Third, to assess individual air pollution exposure levels, we considered the exposure assessment at the community level using residential postal code districts instead of a more accurate exposure estimate for each participant, because there is not enough relevant data in this population. This method of data collection did not allow us to examine the potential roles of multiple factors, such as occupational characteristics or exposure to air pollution in indoor spaces, residence history, nearness to road traffic conditions, local topography, and change in climate. In this context, each subject's level of exposure to air pollution may have been overestimated or underestimated, which may have contributed to potential misclassification of air pollution exposure. Fourth, it is not possible to determine the temporal consistency between exposure and effects for association analysis. In addition, iodine nutrition, which is known to affect thyroid hormones, could not be included as a confounder due to lack of relevant information. Finally, further research on the short-term effect via lag analysis or association with air pollution in FT₃ is needed.

Our data suggest that, in general adult men in Korea, people with high abdominal adiposity may be more vulnerable to increase in TSH and decrease in FT₄ concentrations when exposed to air pollution. The relationship between air pollution exposure and thyroid hormone seems to differ according to the abdominal adiposity distribution, especially VAT level. Our results provide the first clue that long-term exposure to air pollutants is related to the thyroid hormones in Korean male adults and that the relationship may be modified by abdominal adiposity, especially visceral fat level. Further studies are needed to investigate whether the relationship between air pollution, thyroid hormone, and abdominal fat distribution are causal.