Karen P. Phillips

Human Exposure to Endocrine Disrupters and Semen Quality

Reproductive pathology in the male represents about 20% of infertility cases. Male infertility may be attributed to a number of causes, including genetic and congenital abnormalities, infection, multisystemic diseases, varicocele, and others; however, a significant number of cases are idiopathic. Global declines in semen quality were suggested to be associated with enhanced exposure to environmental chemicals that act as endocrine disrupters as a result of our increased use of pesticides, plastics, and other anthropogenic materials. A significant body of toxicology data based upon laboratory and wildlife animals studies suggests that exposure to certain endocrine disrupters is associated with reproductive toxicity, including (1) abnormalities of the male reproductive tract (cryptorchidism, hypospadias), (2) reduced semen quality, and (3) impaired fertility in the adult. There is, however, a relative paucity of studies designed to measure exposure to endocrine disrupters on semen quality parameters (sperm concentration, motility, morphology). An overview of the human semen quality literature is presented that examines the role of endocrine disrupters including organochlorines (OC), dioxins, phthalates, phytoestrogens, and chemical mixtures (pesticides and tobacco smoke).

Risk Factors for Ovarian Cancer: An Overview with Emphasis on Hormonal Factors

Ovarian cancer is the fifth most frequently occurring cancer among women and leading cause of gynecological cancer deaths in North America. Although the etiology of ovarian cancer is not clear, certain factors are implicated in the etiology of this disease, such as ovulation, gonadotropic and steroid hormones, germ cell depletion, oncogenes and tumor suppressor genes, growth factors, cytokines, and environmental agents. Family history of breast or ovarian cancer is a prominent risk factor for ovarian cancer, with 5–10% of ovarian cancers due to heritable risk. Reproductive factors such as age at menopause and infertility contribute to greater risk of ovarian cancer, whereas pregnancy, tubal ligation, and hysterectomy reduce risk. Oral contraceptive (OC) use has clearly been shown to be protective against ovarian cancer. In contrast, large epidemiologic studies found hormone replacement therapy (HRT) to be a greater risk factor for ovarian cancer. The marked influence of hormones and reproductive factors on ovarian cancer suggests that endocrine disrupters may impact risk; however, there is a notable lack of research in this area. Lifestyle factors such as cigarette smoking, obesity, and diet may affect ovarian cancer risk. Exposure to certain environmental agents such as talc, pesticides, and herbicides may increase risk of ovarian cancer; however, these studies are limited. Further research is needed to strengthen the database of information from which an assessment of environmental and toxicological risk factors for ovarian cancer can be made.

Review of the Etiology of Breast Cancer with Special Attention to Organochlorines as Potential Endocrine Disruptors

Breast cancer is the most frequently diagnosed cancer among Canadian women, accounting for about 30% of all new cancer cases each year. Although the incidence of breast cancer has increased over the past 50 years, the cause of this rise is unknown. Risk factors for breast cancer may be classified into four broad categories: (1) genetic/familial, (2) reproductive/hormonal, (3) lifestyle, and (4) environmental. Established risk factors for breast cancer include older age, later age at first full-term pregnancy, no full-term pregnancies, postmenopausal obesity, and genetic factors. However, these known risk factors cannot account for the majority of cases. In the early 1990s, it was suggested that exposure to some environmental chemicals such as organochlorine compounds may play a causal role in the etiology of breast cancer through estrogen-related pathways. The relationship between organochlorines and breast cancer risk has been studied extensively in the past decade and more, and at this point there is no clear evidence to support a causal role of most organochlorine pesticides in the etiology of human breast cancer, but more evidence is needed to assess risk associated with polychlorinated biphenyls (PCBs). Future studies need to consider the combined effects of exposures, concentrate on vulnerable groups such as those with higher levels of exposure, only consider exposures occurring during the most etiologically relevant time periods, and more thoroughly consider gene–environment interactions.

Key Developments in Endocrine Disrupter Research and Human Health

Environmental etiologies involving exposures to chemicals that mimic endogenous hormones are proposed for a number of adverse human health effects, including infertility, abnormal prenatal and childhood development, and reproductive cancers (National Research Council, 1999; World Health Organization, 2002). Endocrine disrupters represent a significant area of environmental research with important implications for human health. This article provides an overview of some of the key developments in this field that may enhance our ability to assess the human health risks posed by exposure to endocrine disrupters. Advances in methodologies of hazard identification (toxicogenomics, transcriptomics, proteomics, metabolomics, bioinformatics) are discussed, as well as epigenetics and emerging biological endpoints.

Assessing and Managing Risks Arising from Exposure to Endocrine-Active Chemicals

Managing risks to human health and the environment produced by endocrine-active chemicals (EAC) is dependent on sound principles of risk assessment and risk management, which need to be adapted to address the uncertainties in the state of the science of EAC. Quantifying EAC hazard identification, mechanisms of action, and dose-response curves is complicated by a range of chemical structure/toxicology classes, receptors and receptor subtypes, and nonlinear dose-response curves with low-dose effects. Advances in risk science including toxicogenomics and quantitative structure–activity relationships (QSAR) along with a return to the biological process of hormesis are proposed to complement existing risk assessment strategies, including that of the Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC 1998). EAC represents a policy issue that has captured the publics fears and concerns about environmental health. This overview describes the process of EAC risk assessment and risk management in the context of traditional risk management frameworks, with emphasis on the National Research Council Framework (1983), taking into consideration the strategies for EAC management in Canada, the United States, and the European Union.

Intracellular pH change does not accompany egg activation in the mouse

In the sea urchin, some other marine invertebrates, and the frog, Xenopus, egg activation at fertilization is accompanied by an increase in intracellular pH (pHi). We measured pHi, in germinal vesicle (GV)‐intact mouse oocytes, ovulated eggs, and in vivo fertilized zygotes using the pH indicator dye, SNARF‐1. The mean pHi was 6.96 ± 0.004 (± SEM) in GV‐intact oocytes, 7.00 ± 0.01 in ovulated, unfertilized eggs, and 7.02 ± 0.01 in fertilized zygotes, indicating no sustained changes in pHi after germinal vesicle breakdown (GVBD) or fertilization. To examine whether transient changes in pHi occur shortly after egg activation, mouse eggs were parthenogenetically activated by 7% ethanol in phosphate buffered saline (PBS); no significant change in pHi followed ethanol activation. Since increased Na+/H+ antiporter activity is responsible for pHi increase in the sea urchin, pHi was measured in the absence of added bicarbonate or CO2 la condition under which the antiporter would be the only major pHi regulatory mechanism able to operate, since the others were bicarbonate‐ dependent) in GV‐intact oocytes, ovulated eggs, and in vivo fertilized zygotes to determine whether a Na+/H+ antiporter was activated. There was no physiologically significant difference in pHi after GVBD or fertilization, when pHi was measured in bicarbonate‐free medium, nor any change upon parthenogenetic activation. Thus, a change in pHi is not a feature of egg activation in the mouse.

A qualitative study of Ottawa university students’ awareness, knowledge and perceptions of infertility, infertility risk factors and assisted reproductive technologies (ART)

BackgroundAwareness of infertility risk factors is an essential first step to safeguard future fertility. Whereas several studies have examined university students’ awareness of female fertility and related risk factors, the topic of male infertility has not been well examined. The objective of this study was to assess young men and women’s awareness, knowledge and perceptions of infertility, male and female infertility risk factors and assisted reproductive technologies (ART).MethodsSemi-structured interviews were conducted in 2008 with a multi-ethnic sample of sixteen male and twenty-three female Ottawa university students, followed by qualitative data analysis to identify major themes. Interview topics included awareness of male and female infertility risk factors, infertility diagnosis/treatments and personal options in the event of future infertility.ResultsParticipants were generally familiar with infertility as a biomedical health problem, could identify sex-specific risk factors but overestimated fertility of women in their thirties and ART success rates. Reproductive health knowledge gaps and confusion of the physiological life-stage of menopause with infertility were apparent. Most participants would pursue in vitro fertilization or international adoption in the event of personal infertility. Some participants wished to use a ‘natural’ approach and were concerned with potential side effects of ART-related medications.ConclusionsThe general awareness of infertility in young adults is promising and supports the potential uptake for health promotion of fertility preservation. This study underscores the continued need for comprehensive sexual and reproductive health education and promotion for adolescents and young adults.

Differences in Intracellular pH Regulation by Na+/H+ Antiporter among Two-Cell Mouse Embryos Derived from Females of Different Strains

Abstract Regulation of intracellular pH (pHi) by two-cell-stage embryos derived from female mice of three different strains (CF-1, Balb/c, and BDF) was investigated. Embryos recovered at a slow rate from intracellular acidosis produced by a pulse of NH4Cl; the rate did not differ significantly among strains. Recovery was reversibly inhibited by amiloride or the absence of Na+, implicating Na+/H+ antiporter activity. The threshold pHi (setpoint) below which Na+/H+ antiporter activity was elicited was approximately 7.15 for each strain. No recovery from induced acidosis occurred in the absence of external Na+ in any strain, and thus embryos could be maintained in acidosis for an extended period. Upon reintroduction of Na+, embryos derived from either CF-1 or BDF females recovered at a slow rate comparable to that measured in embryos not maintained for a period in Na+-free medium, but embryos derived from Balb/c females consistently recovered at a highly accelerated rate. This accelerated recovery appeared to be due, in part, to an activation of the Na+/H+ antiporter in Balb/c-derived embryos, which did not occur in CF-1- or BDF-derived embryos. Thus, embryos derived from different strains of female mice differ in their control of mechanisms for pHi regulation.

Mechanisms of obesity-induced male infertility

Male infertility, characterized by hypogonadism, decreased semen quality or ejaculatory dysfunction, accounts for approximately 20% of infertility cases. Obesity and metabolic dysfunction have been identified, among other causal factors, to contribute to male infertility. In the context of the Western world’s ‘obesity epidemic’, this article discusses three main biological mechanisms linking obesity to impaired male reproductive function: hypogonadism, testicular heat stress/hypoxia-induced apoptosis and endocrine disruption by ‘obesogens’. Among these, obesity-induced hypogonadism is undoubtedly the most clinically significant and is easily assessed. Rapidly expanding areas of research in this area include leptin modulation of kisspeptins and hypothalamic–pituitary–testicular hormone pathways, and roles of other adipocytokines in male infertility, as well as the impact of exposure to obesogens on the quality of semen.

Risk communication of endocrine-disrupting chemicals: improving knowledge translation and transfer.

Public perception of the negative effects of endocrine-disrupting chemicals appears to be higher compared to other chemical pollutants, due to (1) chronic, low-probability effects, and (2) uncertainties about which biological effects may be relevant for human health. Individuals, both expert and lay public, require credible, trustworthy, and understandable information about the scientific evidence of endocrine-disrupting chemicals in order to make informed risk decisions. The creation of a dedicated web site, http://www.emcom.ca, as a tool for knowledge translation and transfer provides the general public with access to scientific experts and bridges the gap between experts and nonexperts through a two-way, interactive communications approach. By obtaining accurate and credible information, individuals can make better-informed decisions concerning endocrine-disrupting chemicals.