Developmental Exposure to Polychlorinated Biphenyls Influences Stroke Outcome in Adult Rats

Neonatal factors can cause latent functional changes that increase susceptibility to disease and/or dysfunction later in life. This hypothesis of the “developmental origins of adult disease” was originally derived from studies that identified stroke as one of several cardiovascular diseases associated with low birth weight (McMillen and Robinson 2005; Morley 2006). Subsequently, brief separations of infant mice from their mothers were demonstrated to increase their sensitivity to cerebral ischemic injury as adults, an effect mediated by functional changes in the hypothalamic–pituitary axis and inflammatory response (Craft et al. 2006). Recent evidence linking developmental exposure to environmental contaminants of concern to neurodegenerative diseases (Barlow et al. 2007; Bolin et al. 2006; Zawia and Basha 2005) suggests a third category of neonatal factors that influences susceptibility of the adult brain to injury, but whether these factors influence adult sensitivity to stroke has not been investigated. Polychlorinated biphenyls (PCBs) are organic compounds that were used mostly as coolants and lubricants from the 1930s until 1977, when they were banned. Despite the ban, PCBs persist in environmental samples, and high residue levels are still detected in foods, particularly fish (Kostyniak et al. 2005; Stewart et al. 1999), and in human tissue samples (Chu et al. 2003; Covaci et al. 2002; DeCaprio et al. 2005; Jursa et al. 2006). Epidemiologic and laboratory evidence suggests that PCBs increase the incidence of risk factors for stroke such as diabetes (Everett et al. 2007; Longnecker and Daniels 2001; Vasiliu et al. 2006) and vascular disease (Carpenter 2006; Hennig et al. 2005); also, living near hazardous waste sites contaminated with PCBs was recently linked to increased stroke incidence (Shcherbatykh et al. 2005). However, these studies did not address whether PCBs influence stroke outcome (the extent of damage occurring after a stroke) nor did they consider the contribution of developmental exposure to PCBs in determining adult susceptibility to cerebral ischemia. The developing nervous system is particularly sensitive to PCBs (Carpenter 2006; Schantz et al. 2003), and in experimental models, exposure of the developing brain to PCBs alters gene expression (Basha et al. 2006) and seizure susceptibility (Pessah IN, personal communication) in the adult brain. Factors known to influence stroke outcome include estrogen (Hurn et al. 2005) and preconditioning, a well-described phenomenon in which exposure to a mild ischemic or noxious stress up-regulates endogenous anti-oxidant and anti-inflammatory mechanisms to protect the brain against subsequent more severe ischemic injury (Koerner and Alkayed 2007). Although mechanisms of preconditioning are not completely understood, de novo gene expression in the brain is clearly required. Bcl2 (B-cell leukemia/lymphoma 2) and Cyp2C11 (cytochrome P450 2C11) are two genes whose up-regulation has been functionally implicated in preconditioning (Koerner and Alkayed 2007). Bcl2 protects neurons against ischemic injury via its anti-apoptotic activity (Kitagawa 2007; Mattson 2007), and CYP2C11 metabolizes arachidonic acid to expoxyeicosatrienoic acids, which are thought to protect against cerebral ischemia via vasodilatory, anti-inflammatory and antioxidant activities (Koerner and Alkayed 2007). Developmental PCB exposure modulates systemic (Meerts et al. 2004) and brain (Colciago et al. 2006) levels of estrogen, increases Bcl2 expression in adult testes (Hsu et al. 2007), and increases expression and activity of hepatic Cyp2C11 (Chen et al. 1992; Kramer et al. 1999). These observations suggest that developmental exposure to PCBs may alter stroke outcome. We tested this hypothesis using a well-established animal model of focal cerebral ischemia to quantify brain infarction in rats exposed throughout gestation and lactation to the commercial PCB mixture Aroclor 1254 (A1254). Although our findings are paradoxical in that developmental PCB exposure was observed to protect against stroke damage, they are of public health significance in that they identify developmental exposures to environmental contaminants as potentially significant determinants of adult susceptibility to cerebral ischemia.