CAN HEAVY METAL EXPOSURE HARM REPRODUCTIVE HEALTH?

Infertility, or failure to achieve clinical pregnancy after 1 year of unprotected intercourse, affects up to 15% of couples worldwide. Estimated US prevalence of women with impaired fertility has increased from 4.5 million in the early 1980s to ~7.7 million by 2025.

Most women with infertility have reproductive or neuroendocrine disorders, such as premature ovarian insufficiency, oligomenorrhea or amenorrhea, anovulation, poor gamete quality, and other reproductive diseases. Mechanisms of women’s infertility may include genetic factors and exposure to reproductive toxicants, such as heavy metals increasingly released into the environment by industrial development, agricultural practices, and production and use of consumer products.

Study Synopsis and Perspective

Background

• Infertility in women has been attributed to both genetic factors and exposure to reproductive toxicants.
• Cadmium, lead, and mercury are 3 primary heavy metals listed by the World Health Organization (WHO) as being among the top 10 toxicants of major public health concern.
• Women’s reproductive health is vulnerable to environmental toxins, particularly endocrine-disrupting chemicals that interfere with the body’s normal hormone synthesis, secretion, and signaling.
• Growing epidemiological and experimental evidence links heavy metals to endocrine-disrupting properties, suggesting a possible causal relationship with women’s infertility and other reproductive disorders.
• Most previous studies have had small sample sizes and have focused on a single metal.

Study Design 

• Data were analyzed for women of reproductive age who participated in the 2013 to 2018 National Health and Nutrition Examination Survey (NHANES) and had blood heavy metals data, including 1999 patients for the comparison of ever-infertile (238 patients) versus fertile (1761 patients) patients and 297 patients for the comparison of ever-infertile (238 patients) versus pregnant (59 patients) patients.
• Multiple logistic regression models were used to examine the associations.

Key Results 

• there was a positive association between lead concentrations and women’s ever-infertility: As blood lead concentrations increased, women were more likely to be ever-infertile (odds ratio [OR], 1.75) versus fertile and ever-infertile (OR, 3.09) versus pregnant.
• No differences were seen for cadmium and mercury concentrations.
• For the analysis of ever-infertile versus pregnant patients, blood concentrations of lead in quartiles 3 and 4 were significantly associated with women’s historical infertility (OR, 3.47 and 5.26, respectively), with a dose-dependent relationship seen from quartiles 2 to 4.

Disclosures

Study Highlights

• Using NHANES 2013 to 2018, 1999 women were identified for analysis of infertility (238 ever-infertile; 1761 fertile) and 1,919 for analysis of long-term amenorrhea. 
• Percentages of women who exceeded typical or normal levels of blood heavy metals were 18.5% for lead, 0.05% for cadmium, and 0.9% for mercury.
• Blood concentrations of lead and heavy metal mixtures were significantly higher in ever-infertile women than pregnant women, but concentrations of cadmium and mercury were similar.
• There was a significant and dose-dependent positive association between blood lead concentrations and women’s historical infertility, a negative association between cadmium and long-term amenorrhea, and no associations between mercury and heavy metal mixture and women’s infertility
• As blood lead concentrations increased, women were more likely to be ever-infertile than fertile (OR, 1.75) or pregnant (OR, 3.09).
• For analysis of ever-infertile vs pregnant, lead blood concentrations in quartiles 3 and 4 were significantly associated with women’s historical infertility
• The investigators concluded that significant percentages of women had blood heavy metal levels exceeding typical or normal levels, that blood concentrations of single lead and heavy metal mixtures were associated with increased historical infertility,
• Female reproductive health is vulnerable to environmental toxins, particularly heavy metals and other endocrine-disrupting chemicals interfering with normal hormone synthesis, secretion, and signaling.
• Overall, the risk for heavy metal exposure to women’s reproductive health and fertility mandates prevention and reduction of heavy metal exposure, which is an urgent, unmet need.
• Genetic factors and reproductive toxicant exposure may both contribute to female infertility. 
• WHO’s top-10 list of toxicants of major public health concern includes cadmium, lead, and mercury.
• As animal studies found that cadmium may adversely affect female reproduction, the finding that cadmium was protective against long-term amenorrhea was unanticipated.
• Future research is needed to evaluate associations among cadmium levels, dietary patterns, iron levels, and amenorrhea.
• Experimental research suggests that lead may affect female fertility via various mechanisms, including menstrual cycle disruption, altered hormone levels, and impaired fetal development.
• In mouse models, lead accumulates in the ovary and disrupts folliculogenesis, reduces ovarian reserve, and increases follicle atresia, all of which may contribute to lead-induced historical infertility.
• Evidence is insufficient to draw meaningful conclusions about how mercury affects female reproductive outcomes, highlighting the need for additional research.

Clinical Implications

• Exposure to heavy metals had differential associations with women’s infertility and long-term amenorrhea.
• Overall, the risk for heavy metal exposure to women’s reproductive health and fertility mandates prevention and reduction of heavy metal exposure, which is an urgent, unmet need.
• Implications for the Health Care Team: Members of the healthcare team should educate women of childbearing age about the risks posed by exposure to heavy metals, including cadmium, lead and mercury.

The study covered in this summary was published in medRxiv as a preprint and has not yet been peer reviewed.^[1]

• Study funding: National Institutes of Health (NIH).
• Author disclosures: NIH, one author received start-up funds from the Environmental and Occupational Health Sciences Institute at Rutgers University.