In this study, we determined the effect exposure to cadmium has on AMH levels in premenopausal women. Our results suggest that cadmium exposure affects AMH concentration depending on the specific age group. When cadmium concentration is increased, the concentration of AMH is decreased in the age group of 30–35-year age group.
Very few previous epidemiologic studies have been conducted on the correlation between cadmium exposure and AMH concentrations in women. An earlier study, which examined the effect of cadmium exposure on AMH concentrations among 117 women, found that cadmium exposure had a positive association with AMH concentration in borderline statistically significant [
15]. However, our findings differ from the findings of that earlier study because the characteristics of the subjects in both studies were very heterogeneous. There are many differences between the two studies, including the distribution of the subjects' age, cadmium concentration, and AMH concentration. In the earlier study, the mean age of the subjects was 26.5 ± 5.6, the median AMH concentration was 11.71 (1.00–123.29), and the median cadmium concentration was 0.46 (0.17–2.98). However, in our study, the mean age of subjects was 36.22 ± 3.86, the median AMH concentration of 3.62 (1.88–6.01), and the median cadmium concentration was 0.96 (0.77–1.22). In particular, age has been known to be a crucial determinant of cadmium exposure and AMH concentration, respectively. As age increases, exposure to cadmium increases and the concentration of AMH decreases [
1,
16]. Because the age range in the earlier study is about 10 years lower than the age range in our research; the cadmium concentrations were lower and AMH concentrations were higher in their study than in our research. In addition, given that the concentrations of cadmium and AMH vary with age, it is more reasonable to analyze the relationship between cadmium and AMH at similar ages after stratification. On the other hand, several studies have determined the effect of cadmium exposure on the reproductive system in men. A current review has outlined epidemiological observational findings for environmental and occupational exposure in humans through experimental studies in humans and animals [
8]. These reports suggested that cadmium causes structural damage to testis vascular endothelium, which ultimately results in necrosis of the testis as well as affecting the blood-follicle-barrier (BFB) integrity, possibly leading to the development of autoimmunity against germ cells. Furthermore, cadmium might affect both spermatogenesis and testis by directly affecting inflammation mediators as well as pro-apoptotic and anti-apoptotic factors. In an in vitro study on pre-pubertal pig testis, Sertoli cell culture has shown that CdCl2 can adversely affect cell viability in a dose-dependent and time-dependent manner. The results showed that CdCl2 treatment can induce impaired function of the Sertoli cells as demonstrated by the reduction in INH-B and AMH secretion. CdCl2 also disrupts FSH receptor responsiveness (measured by a reduction in E2 production) and induces cell apoptosis. [
17]. The molecular weight of AMH is 140 kDa. It is semi-restricted by normal functioning BFB. The disruption of the BFB could potentially cause an increase in the release of AMH from the follicles to circulation, thus theoretically explaining the increase in serum AMH in males [
18]. The present study confirmed that cadmium exposure could affect AMH levels in women, similar to in men. The effect of cadmium exposure on the AMH concentration was also affected based on the age of the subjects. It is known that cadmium can alter the cycle pattern of oxidoreductase gene expression. Cadmium can also alter the clock gene in the neuroendocrine axis because it induces oxidative stress and regulates daily changes in HHG axis activity [
19]. A separate review has outlined cadmium-induced neuroendocrine disruption of the hypothalamus-pituitary-gonad (HHG) axis [
3]. Cadmium interferes with the regulatory mechanisms of this physiological axis by altering the neurotransmitters involved at the hypothalamic level, changing gonadotropin hormone secretion, and affecting testicular or ovarian structure and activity. These effects can be related to the periodic rhythm of the physiological axis associated with aging. Thus, there was also a study about cadmium toxicity, depending on age, in male rats. According to this study, the accumulation of cadmium in the hypothalamus, pituitary gland, and testis varied according to age. Cadmium accumulated in the three organs of young adult male rats but not in the hypothalamus and pituitary glands of older male rats. When they were exposed to cadmium, norepinephrine, dopamine and serotonin metabolism in the hypothalamus. Also levels of plasma LH and testosterone were different in young and old male rats. Thus, the study reported that the neurochemical levels of male rats and daily toxicity of cadmium in the reproductive axis were different in young and old rats. Since our study involved only women, it is difficult to interpret it with regard to previous studies. However, the results showed statistically different significance by age group. This suggests that there may be an association between AMH and cadmium only at a particular age, or there may be a difference in the mechanism depending on age, as a reference.
In this study, we surveyed the subject's history of disease through questionnaires. Pelvic ultrasonography was used in order to determine any gynecologic diseases. In addition, environmental exposures were determined for subjects. These were the key strengths of this study. However, this study has limitations. First, it was a cross-sectional study that could not take time into consideration. In addition, all participants were healthy volunteers which might create bias research results. Although we have adjusted for the possible confounding effects of a number of covariates, there is always the possibility of remaining residual confounders, such as unmeasured grain intake in this study. It is also important to consider endocrine disruptors (ECDs), such as BPA and phthalates which are known to affect vital hormones, in examining the effects of heavy metals and hormones. Bias, such as co-exposure or collinearity, are well-known problems in epidemiological analysis. They occur because of a very high correlation due to common causes, such as shared cause, metabolic pathway, and other factors [
20]. Therefore, the present study first identifies the single effects of cadmium and AMH; it then confirms the subsequent effects of the multi-pollutant approach (such as lasso, PCA, and factor analysis) on the combined effect of cadmium and ECDs on AMH [
21].