Interactions between cadmium and micronutrients in pregnant and lactating women

The heavy metal cadmium is a widely dispersed environmental pollutant that has no biological function in the human body and is known to cause several adverse health effects, mainly on kidneys and bone and the endocrine system. Little is known about effects in early life. The main source of exposure in a non-smoking population is via basic foods such as cereals (e.g. wheat and rice) and vegetables. In adults, the gastrointestinal absorption of cadmium is generally low (<5%), but appears to vary depending on the type of diet consumed and the nutritional status of the individual. Increased absorption of cadmium at low iron stores has been documented both in experimental- and epidemiological studies, while interactions with other essential micronutrients (e.g. zinc and calcium) have been reported in experimental studies only.

The overall aim of the present thesis was to assess the maternal and early life exposure to cadmium with particular focus on the interactions with different essential micronutrients in pregnant and lactating women. The studies were nested into a large food and micronutrient supplementation trail conducted on pregnant women in a rural area of Bangladesh called Matlab. Most of the women in this area are malnourished and their main staple food is rice, known to easily take up cadmium from soil, suggesting that these women are at risk of increased uptake and accumulation of cadmium.

Maternal cadmium exposure was assessed via measurements of concentrations in maternal urine and blood (erythrocyte fraction), while the early life exposure was assessed via measurements in umbilical cord blood and breast milk. Besides cadmium, several nutritional markers were measured in blood, placenta and breast milk. Most of the measurements were performed using inductively coupled plasma mass spectrometry (ICPMS) after microwave assisted high temperature acid digestion (all samples but urine).

The results from the present studies show that women (aged 14 to 44 years) in rural Bangladesh have elevated cadmium exposure. In fact, the urinary cadmium concentrations were similar to those associated with increased risk of adverse health effects on kidneys and bone in other countries. As none of the Bangladeshi women were smokers the main source of exposure is likely food, probably rice.

Women with low iron stores had significantly higher uptake and accumulation of cadmium, indicating increased intestinal uptake of cadmium via the intestinal iron transporters divalent metal transporter 1 (DMT1) and ferroportin 1 (FPN1). Also, the intestinal uptake of cadmium was significantly increased during pregnancy, especially in women with low iron stores. A new finding in the present study is the strong positive association between cadmium and manganese in blood. This is most likely explained by the fact that manganese, like iron and cadmium, is transported via DMT1, leading to a parallel intestinal uptake of these three metals via DMT1. There was no evidence of cadmium uptake via zinc transporters. However, the increased intestinal uptake and accumulation of cadmium at low iron stores was more pronounced among women with adequate zinc status, indicating that zinc is important for the regulation of DMT1. In addition, cadmium appeared to inhibit the transport of calcium to blood.

The cadmium concentration in umbilical cord blood was low, but increased with increasing maternal exposure. There was an accumulation of cadmium in the placenta, which resulted in impaired zinc transfer to the developing offspring. The potential developmental consequences of this need further investigation. The mechanisms behind the interaction between cadmium and zinc in placenta are not known, but the present study indicated that it might be mediated via other mechanisms than the previously proposed binding to metallothionein (MT).

The transfer of cadmium to breast milk was low, but seemed to be mediated via the active transport system utilized by iron and manganese. In addition, cadmium appeared to impair calcium transport in the mammary gland, like in the intestine, possibly by blocking calcium channels and/or by binding to calcium transporters.

List of scientific papers

I. Kippler M, Ekström EC, Lönnerdal B, Goessler W, Akesson A, El Arifeen S, Persson LA, Vahter M (2007). Influence of iron and zinc status on cadmium accumulation in Bangladeshi women. Toxicol Appl Pharmacol. 222(2): 221-6. Epub 2007 May 1
https://pubmed.ncbi.nlm.nih.gov/17543360

II. Kippler M, Goessler W, Nermell B, Ekström E-C, Lönnerdal B, El Arifeen S, Vahter M (2009). Factors influencing intestinal cadmium uptake in pregnant Bangladeshi women A prospective cohort study. [Submitted]

III. Kippler M, Lönnerdal B, Goessler W, Ekström EC, Arifeen SE, Vahter M (2009). Cadmium interacts with the transport of essential micronutrients in the mammary gland - a study in rural Bangladeshi women. Toxicology. 257(1-2): 64-9. Epub 2008 Dec 14
https://pubmed.ncbi.nlm.nih.gov/19126424

IV. Kippler M, Hoque AMW, Raqib R, Öhrvik H, Ekström E-C, Vahter M (2009). Accumulation of cadmium in human placenta interacts with the transport of micronutrients to the fetus. [Manuscript]