Sex Differences in Neurotoxicogenetics

The main risk factors for developing Alzheimer's disease (AD) are age and gender. The incidence of the disease is higher in women than in men, and this cannot simply be attributed to the higher longevity of women versus men. Thus, there must be a specific pathogenic mechanism to explain the higher incidence of AD cases in women. In this regard, it is notable that mitochondria from young females are protected against amyloid-beta toxicity, generate less reactive oxygen species, and release less apoptogenic signals than those from males. However, all this advantage is lost in mitochondria from old females. Since estrogenic compounds protect against mitochondrial toxicity of amyloid-beta, estrogenic action may be important in protecting cells from amyloid-beta toxicity and suggests a possible treatment or prevention strategy for AD. Unfortunately, to date, clinical trials with Ginkgo biloba and other estrogenic therapies have not proved successful in treating AD. As such, more experiments and clinical trials are indeed warranted to find conditions in which estrogenic compounds may be useful to prevent or treat AD.

There is increasing evidence that health effects of toxic metals differ in prevalence or are manifested differently in men and women. However, the database is small. The present work aims at evaluating gender differences in the health effects of cadmium, nickel, lead, mercury and arsenic. There is a markedly higher prevalence of nickel-induced allergy and hand eczema in women compared to men, mainly due to differences in exposure. Cadmium retention is generally higher in women than in men, and the severe cadmium-induced Itai-itai disease was mainly a woman's disease. Gender differences in susceptibility at lower exposure are uncertain, but recent data indicate that cadmium has estrogenic effects and affect female offspring. Men generally have higher blood lead levels than women. Lead accumulates in bone and increased endogenous lead exposure has been demonstrated during periods of increased bone turnover, particularly in women in pregnancy and menopause. Lead and mercury, in the form of mercury vapor and methylmercury, are easily transferred from the pregnant women to the fetus. Recent data indicate that boys are more susceptible to neurotoxic effects of lead and methylmercury following exposure early in life, while experimental data suggest that females are more susceptible to immunotoxic effects of lead. Certain gender differences in the biotransformation of arsenic by methylation have been reported, and men seem to be more affected by arsenic-related skin effect than women. Experimental studies indicate major gender differences in arsenic-induced cancer. Obviously, research on gender-related differences in health effects caused by metals needs considerable more focus in the future.

Epidemiological studies demonstrated an association between increased levels of ambient air pollution particles and human morbidity and mortality. Production of oxidants, either directly by the air pollution particles or by the host response to the particles, appears to be fundamental in the biological effects seen after exposure to particulate matter (PM). However, the precise components and mechanisms responsible for oxidative stress following PM exposure are yet to be defined. Direct oxidant generation by air pollution particles is attributed to organic and metal components. Organic compounds generate an oxidative stress through redox cycling of quinone-based radicals, by complexing of metal resulting in electron transport, and by depletion of antioxidants by reactions between quinones and thiol-containing compounds. Metals directly support electron transport to generate oxidants and also diminish levels of antioxidants. In addition to direct generation of oxidants by organic and metal components, cellular responses contribute to oxidative stress after PM exposure. Reactive oxygen species (ROS) production occurs in the mitochondria, cell membranes, phagosomes, and the endoplasmic reticulum. Oxidative stress following PM exposure initiates a series of cellular reactions that includes activation of kinase cascades and transcription factors and release of inflammatory mediators, which ultimately lead to cell injury or apoptosis. Consequently, oxidative stress in cells and tissues is a central mechanism by which PM exposure leads to injury, disease, and mortality.