Metallic Occupational Toxins and Male Infertility

Ian R. Hurley, Ph.D.1 and Susan Benoff, Ph.D.2
1 Collaborating Investigator, Fertility Research Laboratories
North Shore-Long Island Jewish Research Institute
2 Director, Fertility Research Laboratories
North Shore-Long Island Jewish Research Institute
Associate Professor of Obstetrics and Gynecology
NYU School of Medicine

Apart from gender-specific drugs like contraceptives, men are exposed to the same hazardous substances as women. The effects of these exposures can be very different. Men produce massive numbers of sperm, generally more than 10 million per ejaculation, while women produce one (or a few) eggs a month. Women are born with all the eggs they will ever have, but men renew all their sperm every three months. In some ways sperm production is like production of blood cells. In both cases, a very active tissue (bone marrow or testes) contains stem cells that continuously bud off cells that multiply, changing their shape and function with each cell generation, and leading in the end to large numbers of cells (red blood cells or sperm) very different in shape and function from their ancestors.

If an occupational exposure does not kill all the stem cells, semen, like blood, can often recover completely. An incomplete recovery from a toxin affecting red blood cells may leave an individual feeling sick. But since only one sperm is needed to fertilize an egg and most couples expect conception to take some time, a man and his partner may not know that he has recovered, either completely or incompletely, from an occupational exposure to a reproductive toxin.

The most powerful tool of studies of epidemics, comparing a person's symptoms with his or her exposures, is therefore almost useless in studies of male infertility. Instead, occupational male infertility has largely been studied indirectly, by determining the effect of exposures upon number of children, or number of pregnancies in their partners. The exposures themselves are often also studied indirectly, by lumping all persons in an occupational category, for example, welders, irregardless of the differences in other factors that might affect their fertility, for example, cigarette smoking, or exposure to diesel fumes. Such studies are difficult to do well, and few clear conclusions have emerged.

The strongest evidence for specific reproductive effects of toxins come from workers accidentally exposed to high concentrations of a particular chemical for a short period. For example, men working with grain treated with the fungicide ethylene dibromide stopped producing sperm completely. In some cases, sperm production eventually returned to normal; in other cases it did not. As a result, use of this fungicide has been banned, and drinking water sources and plant effluents are regularly monitored for traces of it.

The group of "heavy' metals may represent a greater risk to reproductive health than relatively low-use chemicals like ethylene dibromide. This group includes cadmium (present in tobacco smoke), nickel (used in batteries, and plated onto a number of common articles used in wide variety of occupations), and lead (present in some brass alloys, in solders connecting heating and water pipes and in electronics assembly, as building flashing, formerly widely used in paints and gasoline, and still used in batteries.). These metals have also been dispersed into atmospheric dust arising from industrial processes and from fossil fuel combustion. Dust particles the right size can lodge in lungs, be absorbed into the blood and transported to reproductive organs. Occupational exposures to lead and nickel are well documented to increase the amounts of these metals in men's blood stream and semen. The case of cadmium is less clear, but both some human data and studies of animals exposed to cadmium suggest there are likely to be effects on prostate function.

Development of treatments for infertility, including in vitro fertilization, have lead to development of diagnostic tests, so that couples may be properly advised on courses of treatment that are likely to be successful. Some of these tests, making use of recent advances in the molecular biology of the fertilization process, monitor one or more of a number of molecules involved in normal human sperm function that malfunction, or are absent, in infertile men. These tests have been co-opted for the study of male reproductive toxicants.

Cadmium ions, for example, apparently can enter both mature and immature sperm cells. Once inside, these cadmium ions can cause molecules forming the cellular backbone to spontaneously disassemble. Products of this disassembly can apparently tell the cell to self-destruct. When this occurs inside the testis, the number of sperm produced decrease. In severe cases, this can produce male sterility. Several factors influence the severity of cadmium effects. The level of cadmium in the blood is one factor. A second is the occurrence of varicose veins in the testes. A consequence of these varicose veins appears to be to increase the force driving metal ions from blood into the parts of the testes where sperm develop, thereby increasing the amount of cadmium the developing sperm see. A third factor seems to be the type of calcium ion channel the individual man has on his sperm. Some types are associated with greater sensitivity to cadmium poisoning than others.

Each of these factors can be assessed by a test. Partial disassembly of cellular backbones give sperm a characteristic shape that is apparent in a conventional sperm analysis, at least in cases where sperm production continues at a reduced level. Blood cadmium levels can be measured by a clinical chemistry laboratory. Varicose veins in the testes are routinely identified by palpation or ultrasonography. The cadmium-sensitive types of sperm calcium ion channels can be distinguished by molecular testing.

Other factors are likely to be involved in cadmium's reproductive effects. Calcium acts as a secondary messenger in cells. That is, it carries instructions from cellular surfaces to proteins deep within, starting, stopping or modulating cellular events like mRNA transcription. Genetic variations in these other proteins could conceivably make them more or less sensitive to changes in the signaling that cadmium can disrupt.

Lead seems to affect a different pathway in sperm function. Progesterone, a molecule present in relatively high concentration in the mass of cells that accompany a fertile egg down a woman's Fallopian tubes, seems to act upon sperm through a protein on the sperm head that binds progesterone. The act of binding progesterone seems to prime sperm, so that they can react properly when they touch the egg. Too much progesterone is not a good thing. It causes the sperm to react as if it had already reached the egg surface. So when it does reach the egg, the sperm is not longer fit to bind to the egg and fertilize it. Sperm from infertile men with high lead levels look as if they had seen too much progesterone. Lead appears to be able to enter sperm through this channel. As in the case of the cadmium-sensitive calcium channel, different types of human sperm potassium channel exist, some of which are more sensitive to lead effects than others. Genetic variation between men may also be partially responsible for the severity of the effect that a given blood lead level has upon sperm function.

Other toxic metals are currently under study with similar molecular tools from infertility research. The pattern that seems to be emerging is that, like cancer, male infertility is a multi-hit condition, in which toxic metals interact with genetic variations to produce effects.

Epidemiological studies that make use of these and other emerging tests of intracellular function offer the promise of reliable and accurate measures of individual tolerance levels for metallic toxicants.