Phthalate diesters, widely used in flexible plastics and consumer products, have become prevalent contaminants in the environment. Human exposure is ubiquitous and higher phthalate metabolite concentrations documented in patients using medications with phthalate-containing slow release capsules raises concerns for potential health effects. Furthermore, animal studies suggest that phthalate exposure can modulate circulating hormone concentrations and thus may be able to adversely affect reproductive physiology and the development of estrogen sensitive target tissues. Therefore, we conducted a systematic review of the epidemiological and experimental animal literature examining the relationship between phthalate exposure and adverse female reproductive health outcomes. The epidemiological literature is sparse for most outcomes studied and plagued by small sample size, methodological weaknesses, and thus fails to support a conclusion of an adverse effect of phthalate exposure. Despite a paucity of experimental animal studies for several phthalates, we conclude that there is sufficient evidence to suggest that phthalates are reproductive toxicants. However, we note that the concentrations needed to induce adverse health effects are high compared to the concentrations measured in contemporary human biomonitoring studies. We propose that the current patchwork of studies, potential for additive effects and evidence of adverse effects of phthalate exposure in subsequent generations and at lower concentrations than in the parental generation support the need for further study.

Phthalate diesters are a diverse group of chemicals used to make plastics flexible and are found in personal care products, medical equipment, and medication capsules. Ubiquitous in the environment, human exposure to phthalates is unavoidable; however, the clinical relevance of low concentrations in human tissues remains uncertain. The epidemiological literature was inadequate for prior reviews to conclusively evaluate the effects of phthalates on male reproductive tract development and function, but recent studies have expanded the literature. Therefore, we conducted a systematic review of the literature focused on the effects of phthalate exposure on the developing male reproductive tract, puberty, semen quality, fertility, and reproductive hormones. We conclude that although the epidemiological evidence for an association between phthalate exposure and most adverse outcomes in the reproductive system, at concentrations to which general human populations are exposed, is minimal to weak, the evidence for effects on semen quality is moderate. Results of animal studies reveal that, although DEHP was the most potent, different phthalates have similar effects and can adversely affect development of the male reproductive tract with semen quality being the most sensitive outcome. We also note that developmental exposure in humans was within an order of magnitude of the adverse effects documented in several animal studies. While the mechanisms underlying phthalate toxicity remain unclear, the animal literature suggests that mice are less sensitive than rats and potentially more relevant to estimating effects in humans. Potential for chemical interactions and effects across generations highlights the need for continued study.

BACKGROUND Cigarette smoke is a documented reproductive toxicant associated with infertility and ovarian failure. However, the underlying mechanism(s) regulating the toxic effects of cigarette smoke are unknown. Therefore, we tested the hypothesis that mainstream cigarette smoke and a cigarette smoke constituent, benzo[a]pyrene (BaP), induce apoptosis in ovarian follicles.

Throughout the 1980s and 1990s the crude human birth rate (live births per 1000 population) declined, indicating reduced fertility and suggesting a potential decline in fecundity (the potential to conceive). Detection of environmental contaminants in human tissues, together with reports of a global decline in semen quality, further fueled speculation that human infertility rates are increasing and environmental toxicants are potentially important causal agents associated with this change. However, there is little compelling evidence to suggest that infertility rates amongst the general population have changed over time. Moreover, recent studies suggest a rise in the fertility rates. While several studies documented increased time to pregnancy (TTP) in exposed study populations, other investigators were not able to replicate these findings. Nevertheless, studies involving occupational exposure together with results from animal experiments lend support to the conclusion that environmental contaminants potentially adversely affect fertility. Consequently, the impact of exposure to environmental contaminants on human fertility remains controversial. To test the hypothesis that environmental contaminant exposure was associated with enhanced risk of infertility, data concerning trends in fertility and infertility rates were examined to assess the impact of exposure of developing gametes to environmental contaminants. The relationship between exposure and reproductive outcomes was then examined to illustrate the range of adverse effects for reproductive toxicants with data sets of divergent depth and reliability. Data showed that only a weak association between exposure to environmental contaminants and adverse effects on human fertility exists. However, it is postulated that evidence of chemical exposure and potential health consequences of these exposures highlight the need for further research in this area.

Cigarette smoking is a lifestyle behavior associated with significant adverse health effects, including subfertility and premature ovarian failure. Cigarette smoke contains a number of chemicals, many of which are involved in the generation of reactive oxygen species, which can lead to apoptosis and autophagy. Autophagy is a fundamental process that removes damaged organelles and proteins through lysosomal degradation. The relevance of autophagy to toxicant-induced changes in ovarian function is largely unexplored. Previously, we reported that exposure to cigarette smoke causes follicle loss, oxidative stress, activation of the autophagy pathway, and decreased expression of manganese superoxide dismutase, which points to altered mitochondrial function. Therefore, our objective here was to test whether exposure to cigarette smoke results in the dysregulation of mitochondrial repair mechanisms leading to loss of follicles via autophagy-mediated granulosa cell death. In this study, mice were exposed to cigarette smoke or room air for 8 wk. The expression of genes and proteins of autophagy and mitochondrial repair factors was measured using quantitative real-time PCR and Western blot analysis, immunohistochemistry, and enzyme-linked immunosorbent assay. Increased expression of parkin and decreased expression of the mitofusins suggest that exposure to cigarette smoke triggers mitochondrial damage. Moreover, the autophagy cascade proteins, BECN1 and LC3, were upregulated, whereas the antagonist BCL2 was downregulated, following treatment. Taken together, our results suggest exposure to cigarette smoke induces dysfunction of mitochondrial repair mechanisms, leading to autophagy-mediated follicle death.