Infertility is a significant health problem worldwide, estimated to affect approximately 1:6 couples of reproductive age. Whilst reports of global declines in semen quality are controversial, the increasing prevalence of male subfertility stands as uncontested fact: male factor is now the leading cause of fertility problems, and accounts for almost half of all cases. Exposure to environmental toxicants, such as heavy metals, organic solvents and pesticides, as well as lifestyle choices, including obesity and poor diet, drugs (prescribed medication and otherwise) and smoking are all suggested to be contributory causes to male subfertility, but effects are poorly defined. Unexplained poor sperm motility (asthenozoospermia) is the commonest clinical abnormality in subfertile males, yet our limited knowledge of the exact workings of spermatozoa mean that this problem is incompletely understood, neither do we know how to correct it. Incredibly, there is no drug that a subfertile man can take, nor that can be added to his sperm in vitro, to improve sperm motility. Couples instead rely on Artificial Reproduction Technology (ART), such as IVF, which is expensive, invasive and not without risk. Nonetheless, year-on-year, ART is increasingly utilised worldwide. In order to tackle a global health problem, there is clearly a need to better understand the pathological processes affecting male reproductive health.

Sperm motility, calcium and CatSper

Sperm motility is arguably the most important characteristic to impact on male fertility. Increase and fluxes in intracellular calcium [Ca2+]i are fundamental to the regulation of sperm motility and function, including changes in direction, hyperactivation and chemotaxis. [Ca2+]i is regulated by at least two processes: mobilisation of Ca2+ stored in the sperm neck region and/or movement into the cell via Ca2+ permeable ion channels and transporters, mainly CatSper channels. CatSper channels are essential for male fertility and are present in the flagellum of human sperm. Landmark studies have demonstrated Ca2+ entry into human sperm in response to progesterone (a product of cumulus cells) is via CatSper channels. CatSper channels are also activated by organic molecules that apparently evoke chemotaxis, and it has therefore been proposed that this ion channel acts as a polymodal chemosensor integrating multiple chemical cues from the female reproductive tract to elicit functional responses to direct sperm towards the egg.

Environmental exposures

Xenobiotics are any alien molecules that are foreign to mammalian biological systems. Such substances include pesticides, herbicides, cosmetics, preservatives, cleaning materials and pharmaceutical products, and have worked their way into our lives in a variety of forms. Even though awareness of the biological risks of chemical toxicity has increased considerably in recent years, the majority of these chemicals have long half-lives and can still be detected in the environment decades after their release. Xenobiotics may have direct or indirect effects on sperm motility and function, including interference with physiological CatSper responses, which subsequently manifests as male subfertility. For example, dichlorodiphenyldichloroethylene (DDE) is an organochlorine pesticide, an endocrine disruptor and known reproductive toxicant to certain species of birds due to thinning of their eggshells. DDE is fat soluble, and tends to build up in the fat of animals. Due to its stability in fat, DDE is rarely excreted from the body, and body levels tend to increase throughout life. In vitro exposure to DDE affects functional sperm parameters and we have demonstrated that it activates CatSper at environmentally relevant concentrations.

Trans-generational reproductive impact

For many disease states it is now recognised that the risk of disease in adult life is determined by a combination of genetics, the intra-uterine environment, childhood exposures and adult lifestyle, but the impact of each of these components on sperm parameters and male fertility is largely unknown. The impact of environmental factors on the epigenome and male fertility, and significance of epigenetic changes/aberrations (often hypermethylation) in assisted reproduction are beginning to be understood. However, identification of the respective contribution of genetic and timecourse environmental exposures to male reproductive capacity in adulthood is not only very limited, but also very challenging, particularly due to the difficulty of obtaining data on multiple factors throughout life.

Aims

By utilising the Avon Longitudinal Study of Pregnancy and Children (ALSPAC) cohort, we aim to address the contribution of genetic and timecourse environmental exposures to male reproductive capacity in adulthood. This cohort is a huge resource and has the fantastic potential to provide prospective longitudinal data, allowing not only quantification of relative contributions of various elements, but the potential to identify critical timepoints and how these associations change with progression from fetal life, childhood, adolescence and into adult life.