The effects of prenatal PCBs on female reproduction development, behavior, and gene expression /

by Steinberg, Rebecca Meg

Prenatal exposures to endocrine-disrupting chemicals such as polychlorinated biphenyls (PCBs) can cause latent effects on reproductive function. Here, we tested whether PCBs administered during late pregnancy would compromise reproductive physiology in both the fetally-exposed female offspring (F1 generation), as well as in their female offspring (F2 generation). Pregnant Sprague-Dawley rats were treated with the PCB mixture Aroclor (A) 1221 (0, 0.1, 1 or 10 mg/kg) on embryonic days 16 and 18. Somatic and reproductive development of F1 and their F2 female offspring were monitored, including ages of eye opening, pubertal landmarks, and serum reproductive hormones. The results showed that low doses of A1221 given during this critical period of neuroendocrine development caused differential effects of A1221 on F1 and F2 female rats. No significant differences were observed between treated groups and control in the F1, although the F2 generation showed more profound alterations. In particular, on proestrus, the day of the preovulatory GnRH/LH surge, F2 females exhibited profoundly suppressed LH and progesterone, and correspondingly smaller uterine and ovarian weights on estrus. These latter physiologic changes suggest that the GnRH/LH surge is delayed or abolished in adult F2 female rats whose mothers were fetally exposed to A1221. Thus, low levels of exposure to PCBs during late fetal development cause significant 47 consequences on the maturation and physiology of two generations of female offspring, and these findings have implications for reproductive health and fertility of wildlife and humans. 48 Introduction Polychlorinated biphenyls (PCBs) were used as non-flammable lubricants and insulators in industry beginning in 1929 until they were banned in 1977. Because of their lipophilic structures, PCBs are easily absorbed from the environment into the food chain, rendering human and animal exposure ubiquitous and persistent. As a result, a greater understanding of the many negative outcomes of exposure continues to be essential to human health, and for addressing declining wildlife fecundity and viability. PCB exposure has been linked with a broad spectrum of effects, both invivo and invitro, which vary depending on method/age of exposure, sex of the individual, and dose/duration of exposure. Fetal and early developmental exposure to PCBs is particularly devastating, and can have different outcomes from adult exposure (Crews, et al., 2000). Latent effects of early exposures include, but are not limited to, depressed circulating thyroid hormone and abnormal thyroid cytology (Bansal, et al., 2005, Chauhan, et al., 2000, Goldey, et al., 1995, Morse, et al., 1996c, Porterfield, 1994), delayed cognitive development (Chen, et al., 1992, Jacobson and Jacobson, 1997), altered sensory and motor abilities (Bowman, et al., 1981, Lasky, et al., 2002, Roegge, et al., 2004), reproductive impairment (Arnold, et al., 1995, Meerts, et al., 2004b, Sager and Girard, 1994, Yang, et al., 2005), and compromised neural function (Donahue, et al., 2004, Morse, et al., 1996a, Provost, et al., 1999a, Seegal, et al., 2005). Not only do PCBs and other environmental endocrine disrupting chemicals directly affect the exposed individual, but they can also exert effects on subsequent generations that may differ from those associated with primary exposure (Fernie, et al., 2003, Shipp, et al., 1998). One compelling mechanism for multigenerational effects of PCBs is via the hypothalamicpituitary-gonadal reproductive axis. Exposure of the first generational 49 animals can later result in aberrant reproductive physiology and behavior, including improper steroid hormone production during pregnancy, and deficiencies in parturition, lactation and maternal behavior (Boersma and Lanting, 2000, Takser, et al., 2005). Such alterations can potentially be transmitted to a second generation offspring through improper hormonal exposure while in utero, and altered parental care postnatally (Champagne and Meaney, 2001, Cummings, et al., 2005). Thus PCBs, particularly developmental exposures, can affect the immature organism, adult, and subsequent generations of offspring, although relatively little is known about the nature and mechanisms of these outcomes. The current study investigated the effects of prenatal exposure to PCBs on sexual and somatic development of two generations, employing low, ecologically relevant doses of PCBs (Zhang, et al., 2004). Aroclor (A)1221, a commercial PCB mixture composed of lightly-chlorinated isomers, was chosen for this study because of its previously reported disruption of the neuroendocrine system (Chung and Clemens, 1999, Chung, et al., 2001, Gore, 2001, Gore, et al., 2002, Salama, et al., 2003, Steinberg, et al., 2007, Woodhouse and Cooke, 2004). Materials and Methods