US researchers find first conclusive evidence that lead is linked to male infertility

US fertility experts today (Thursday 6 February) published the first conclusive evidence that lead is linked to male infertility.

A report in Europe’s leading reproductive medicine journal Human Reproduction[1] concludes that exposure to lead damages sperm function and may be a contributory cause of unexplained male infertility.[2]

The findings have led principal investigator Dr Susan Benoff to urge doctors to measure lead in seminal plasma when evaluating men from couples with unexplained fertility. She also believes there is a case for health and safety authorities to continue re-evaluating environmental exposure limits.[3]

Dr Benoff, director of the Fertility Research Laboratories at the North Shore-Long Island Jewish Research Institute in Manhasset, New York, and colleagues from several other US institutions, undertook a prospective, double-blind study of metal ion levels and sperm function in semen from the partners of 140 consecutive women undergoing their first IVF cycle.

They found that lead levels in seminal plasma varied over a wide range and there was a significant association between high lead levels and a low fertilisation rates, with changes in lead levels accounting for a fifth of the variance in fertilisation rates.

“From our tests on lead in the seminal plasma of the participants and control experiments on nine fertile donors, we have evidence that higher lead levels interfere both with the ability of the sperm to bind to the egg and with its ability to fertilise the egg,” said Dr Benoff.

In order to fertilise an egg, a sperm has first to bind to it. A sugar called mannose on the outer coating of the egg is crucial to binding. Mannose receptors located on the head of human sperm recognise the mannose on the coating of the egg and regulate the binding process.

Then the sperm has to penetrate the egg. Successful binding induces an event called mannose-induced acrosome reaction – the release of digestive enzymes from the sperm that ease its passage through the egg coating so that its nucleus can fertilise the egg.

The researchers found that in the 140 men whose partners were undergoing IVF, higher lead levels in the seminal plasma correlated with low expression of mannose receptors and with inability of sperm to undergo mannose-induced acrosome reaction. Conversely, higher lead levels were associated with premature (or spontaneous) acrosome reaction that occurs before sperm-egg contact, also blocking fertilisation.

“To see whether this association between increased lead levels could be causal we exposed healthy sperm from nine fertile donors to increasing doses of exogenous lead to see what would happen. We got the same results,” said Dr Benoff.

“These biomarkers provide relatively unambiguous endpoints for lead-induced reproductive toxicity and our data suggest that lead is acting at multiple levels in testis and sperm to decrease human male fertility.

“Our data also confirm that increased seminal plasma lead levels can occur without any detectable effects on male reproductive hormone function and also that they are associated with decreased sperm concentration, sperm shape, form and movement, suggesting that lead also acts in the testis. Elevated lead levels in rats’ testes are associated with programmed cell death of sperm precursors and studies of men with non-obstructive low or zero sperm counts indicate that programmed cell death in the testes is a major determinant of sperm count in the ejaculate. This leads us to believe that lead is a contributory factor of declining sperm counts.”

She said the findings of high seminal lead levels among the 140 men in the study were unexpected, as lifestyle questionnaires showed that none was engaged in occupations likely to produce exposure to metal ions. High lead levels in up to 29 of the IVF patients were associated with smoking and/or alcohol consumption, but high levels in patients who did not smoke cigarettes or drink alcohol were unexplained. One possibility was lack of exercise (blood lead levels increase with decreased physical activity). Another possibility was a low calcium or high lactose or fat diet, which can enhance lead accumulation. Genetic variation in response to lead exposure may also be a factor as the study revealed some instances of normal fertilisation rates despite high lead levels and reduced fertilisation rates despite low lead levels.

Dr Benoff said it was important that the results should not be construed as evidence of an epidemic of overt lead toxicity as none of the patients showed signs of lead toxicity and it is not yet known if there is a strong correlation between seminal plasma lead levels and lead concentration in the blood (the normal method of measuring lead exposure).

But she warned: “In the light of these results, environmental exposure limits for lead might be re-evaluated.”

She said it was also important that men are often ‘under served’ at fertility clinics. “Our findings emphasise the need for co-operation between reproductive endocrinologists and urologists and a workup of the male partner of infertile couples that is more extensive than a simple semen analysis or measurement of circulating reproductive hormones. We suggest the addition of measurements of the heavy and transition metal ion content of seminal plasma (not blood) and some form of sperm function testing. It must be recognised that treating the male is generally less invasive and less costly than treating the female.”
(ends)

[1] Increased seminal plasma lead levels adversely affect the fertility potential of sperm in IVF. Human Reproduction. Vol. 18. No 2. Pp 374-383.

[2] No apparent explanation for infertility can be found in between 5 and 10% of infertile couples

[3] Lead is ubiquitous, common in the environment and found in many homes e.g. in fixtures and fittings, past use of paints, in alloys, food kept in lead-glazed ceramics, fungicides, petroleum products, agricultural soil, herbal medicines, cigarettes etc. Mean concentrations of lead in bone and soft tissues are higher in men than in women.

Recommended top levels of environmental exposure to lead vary between and even within countries. In the USA the National Institute for Occupational Safety and Health (NIOSH) recommends a limit of under 100 micrograms per cubic metre in air averaged over a time period, while the American Congress of Governmental Industrial Hygienists recommend under 150. But some states have adopted a maximum of 50 micrograms. In Europe, only Poland has set a limit as low as 50 micrograms per cubic metre while most countries have an average of between 100 and 150. Similarly the recommended thresholds for lead in blood also vary and may differ between men and women in some countries.