Gene Expression in Oogenesis and Implications for Transgenerational Effects of Environmental Toxicants

An estimated 50–80 million people worldwide are infertile [1], and of these, an estimated 7.3 million are American women [2, 3]. Despite concern that infertility rates are increasing, recent evidence suggests that the prevalence of infertility is lower than often cited and is similar across developed and developing nations [4]. Established risk factors for this condition include advanced age, diet, prescription medication use, pre-existing health status, and infections; however, the underlying causes of infertility in many reproductive-age couples remain unknown. Of the many environmental toxicants and lifestyle factors that may affect ovarian function and fertility, the estrogenic chemical bisphenol A (BPA) [5, 6] has received considerable media and research attention over the last decade. BPA is present in many commercial products, and trace concentrations are found in food products as a result of incomplete polymerization and exposure to heat, acidic, or alkaline conditions [7–10]. It is not surprising that BPA has been detected in the range of 0.1 to 10 ng/ml in the majority of human body fluid samples tested [11–17]. However, exposure cannot be equated with an adverse effect on health, and the potential for human health effects has been hotly debated. Reports of adverse health effects in the human population are surprisingly rare and statistically underpowered, with weak associations that lack mechanistic insight [18–21]. In comparison, early persistent estrus and meiotic aneuploidy have been shown by several research groups using multiple animal models exposed to BPA [22–25] (for review, see [26, 27]), whereas other groups have been unable to find an adverse effect of BPA on reproductive processes [28–30]. Of note, accidental exposure to BPA had an adverse effect on fertility in mice [23], and a subsequent study demonstrated a subtle effect on meiotic recombination and aneuploidy resulting from low-dose BPA exposure [24]. Regardless, the effect of BPA on oogenesis and reproductive function is incompletely understood. General agreement exists that in mammalian species (and, in particular, humans), oogenesis only occurs early in life, and the resultant pool of oocytes/follicles is then “drawn down” over the life span [31–37]. However, the mechanisms regulating oogenesis and the potential effects of exposure to environmental toxicants on meiotic progression during oogenesis and subsequent oocyte quality and fertility are virtually unknown. Recently, a subtle but significant increase in recombination rates and synaptic defects in pachytene-stage oocytes was found in ovaries from mice exposed to BPA versus controls [24]. A threefold increase in the incidence of subtle synaptic defects and a 10% increase in recombination rates were reported. Because the above effects arise from changes that occur during prophase, one of the earliest phases of meiosis, it was reasoned that BPA exposure could exert its influence on the developing oocyte at premeiotic or early prophase time periods (Fig. 1). Using gene array studies, Lawson et al. [38], in this issue of Biology of Reproduction, identify a family of genes that are potentially important in the earliest stages of oocyte development and define their temporal expression. These genes are involved in meiotic entry, formation of the synaptonemal complex, meiosis-specific cohesions, meiotic recombination pathways, and chromatin remodeling. Of note, low-dose BPA exposure (20 ng [g body wt]−1 day−1 on 11–14.5 days postcoitus) induced down-regulation in the expression of genes from biological processes involved in regulation of the cell cycle, mitosis, and DNA replication. It is not known if the changes in gene expression will translate into functional changes in grandchild fertility or in overall health and fitness. Primordial follicles are formed during the 20th week of gestation in humans and populate the ovary before birth, forming a reserve of follicles for life. Primordial follicles remain quiescent until a small cohort are recruited into the growing pool with each estrous (nonprimate) or menstrual (primate) cycle. The follicle undergoes intense granulosa cell proliferation, oocyte growth, tissue remodeling, and vascularization over the course of follicle development, ovulation, corpus luteum formation, and ultimate regression. During folliculogenesis, the oocyte completes the first meiotic division and only completes the second meiotic division following fertilization and successful oocyte activation. Although environmental contaminants like BPA have been measured in the serum and are distributed throughout body compartments, the period of highest oocyte exposure will potentially occur during completion of the first meiotic division and the start of the second meiotic division. The results reported by Lawson et al. [38] are exciting and suggest yet another consequence of environmental toxicant exposure that could potentially explain adverse effects seen across multiple generations. Toxicant-induced changes in the expression of the genes regulating meiotic progression during oogenesis could have important implications for oocyte competence, fertilization, and thus, subsequent fertility in the offspring and could potentially affect subsequent offspring. However, recent findings call into question the relevance of the observed changes in gene expression. Specifically, in utero BPA exposure, using concentrations that include the low-dose range, had no adverse effect on fertility in the F1 generation, and on litter size in the F2 generation, of Long-Evans rats [29], although significant changes were documented with estradiol exposure in that study. Given that a low-dose concentration of BPA was used, it is conceivable that the effects on gene expression either had no impact on fertility or are species-specific. Hence, it is unclear if the observed changes are limited to mice or can be generalized to other mammals, including humans. Furthermore, biomonitoring studies have shown widespread exposure of the population to numerous chemicals with hormone-like activity in addition to BPA. Therefore, it will be important to determine, first, if exposure to other environmental toxicants induce similar changes to those of BPA and, second, the relative potency as well as the long-term health consequences of these exposures. In summary, these results suggest that regulatory toxicology testing must also consider the potential for low-dose exposures to induce subtle adverse effects on germ cell development and transgenerational effects. Whereas BPA-induced changes in gene expression have the potential to be transferred across generations, the relevance of these results for human development and general health is uncertain. With advances in reproductive biology such as those described above, we can expect exciting times to come as mechanisms regulating key reproductive processes are revealed and new targets for therapeutic intervention and toxicant action are exposed.

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