The Toxic Effect of Environmental Cadmium on Visceral Adipose Tissue

Abstract

Cadmium is an environmental toxin strongly associated with the development of cancer, kidney and liver disease, and bone demineralization. Whether cadmium causes obesity in humans remains a subject of controversy in the literature. An NHANES study that examined the effect of various toxic metals on central obesity demonstrated a decrease in the BMI of subjects exposed to cadmium. The purpose of this study is to examine the effect of cadmium on visceral adipose tissue (VAT), the potential for chelation to reverse cadmium‐induced changes, and to investigate the mechanism by which these changes occur. VAT is the subset of adipose tissue most heavily implicated in the pathogenesis of obesity, insulin resistance, and metabolic syndrome. ICR mice were placed into one of three groups: control, cadmium followed by washout, and cadmium followed by chelation. Mice in the two experimental groups were treated with 100ppm CdCl2 drinking water for 8 weeks followed by either 8 weeks of washout or 8 weeks of chelation with DMSA. Digital analysis of H&E images was performed using ImageJ and morphometric parameters of approximately 400 adipocytes per group were obtained. A 14.6% reduction in adipocyte size was observed in the group treated with cadmium followed by washout relative to the control group (p < 0.0001). In the group that underwent chelation after cadmium exposure, there was an increase in adipocyte size relative to the cadmium‐washout group (p<0.002). Additionally, animals in the cadmium‐washout group had a 5% reduction in body weight relative to control (p<0.0001). There was no significant difference in weight between the control group and the cadmium‐chelation group. In conclusion, the mouse model we have developed demonstrates that chronic low dose cadmium exposure causes weight loss and that chelation has the potential to reverse this change. Although the effect of cadmium on body weight remains controversial, this mouse model may serve to clarify this relationship and address the mechanism of cadmium’s action. Support or Funding Information NIEHS Grant # P30 ES027792‐02

White adipose tissue as a target for cadmium toxicity

“…Our results showed that Cd exposure caused a significant decrease in rats’ body weight. The reduction of the body weight agrees with former studies that recorded Cd exposure caused a downregulation in the body weight of murine ( Kawakami et al, 2010 ; Prabhu et al, 2020 ). The reduction of the body weight in the Cd-T group is suggestive of either losing adipocytes or dysregulated adipogenesis.…”

Adipotropic effects of heavy metals and their potential role in obesity

“…Despite some existing contradictions, the experimental data provide insight into dose-dependent effects of heavy metals on adipogenesis. It is proposed that the effects of heavy metal exposure on adipose tissue is biphasic ( Figure 1 ), varying from increased adipogenesis at low-dose exposure to inhibition of adipose tissue differentiation at higher doses, as demonstrated for Hg 21 , 22 , Cd 55 , 56 , 58 , 59 , and As 41 . However, direct dose-response analysis was performed only for the latter 41 .…”

“…Particularly, a study originating from Mexico City demonstrated an inverse association between maternal urinary Cd levels and abdominal and peripheric adiposity 57 . An experimental in vivo study demonstrated that administration of 100 ppm CdCl 2 in drinking water to ICR mice for 8 weeks resulted in a significant decrease in adipocyte size but that Cd chelation using dimercaptosuccinic acid (DMSA) ameliorated this effect 58 . This effect may be at least partially mediated by the earlier demonstrated Cd-induced (3 μM) inhibition of adipogenesis and a dose-dependent decrease in C/EBPα and PPARγ protein expression in 3T3-L1 preadipocytes 59 .…”

“…The existing experimental studies revealed significant contradictions in the effects of Cd on adiposity and adipogenesis in particular. Hypothetically, “low”-dose exposure in vivo (100 nM CdCl 2 with drinking water, C57BL/6J mice 55 ) and in vitro (0.5–2 µmol/L CdCl 2 , bone marrow adipocytes 56 ) may promote body adiposity through upregulation of adipogenesis, whereas “high” doses studied in ICR mice (100 ppm CdCl 2 in drinking water 58 ) and 3T3-L1 preadipocytes (3 μM 59 ) may reduce adipose tissue levels at least partially through inhibition of adipogenesis.…”

Cadmium: An Emerging Role in Adipose Tissue Dysfunction

“…More exploration was done by the same team, to study the effect of acute Cd exposure in MT-null mice and found that, adipocytes size was significantly reduced (Kawakami et al 2013). In agreement with these results, a recent study reported that mice exposed to Cd for 8 weeks exhibited a significant reduction in both body weight and adipocytes size (Prabhu et al 2020). However, an earlier study that examined the Cd effect on AT using a rat model, reported no changes in both body weight and adipocyte size (Ficková et al 2003).…”