Developmental exposure of rats to chlorpyrifos elicits sex-selective hyperlipidemia and hyperinsulinemia in adulthood - PubMed (original) (raw)

Developmental exposure of rats to chlorpyrifos elicits sex-selective hyperlipidemia and hyperinsulinemia in adulthood

Theodore A Slotkin et al. Environ Health Perspect. 2005 Oct.

Abstract

Developmental exposure to chlorpyrifos alters cell signaling both in the brain and in peripheral tissues, affecting the responses to a variety of neurotransmitters and hormones. We administered 1 mg/kg/day chlorpyrifos to rats on postnatal days 1-4, a regimen below the threshold for systemic toxicity. When tested in adulthood, chlorpyrifos-exposed animals displayed elevations in plasma cholesterol and triglycerides, without underlying alterations in nonesterified free fatty acids and glycerol. This effect was restricted to males. Similarly, in the postprandial state, male rats showed hyperinsulinemia in the face of normal circulating glucose levels but demonstrated appropriate reduction of circulating insulin concentrations after fasting. These outcomes and sex selectivity resemble earlier findings at the cellular level, which identified hepatic hyperresponsiveness to gluconeogenic inputs from beta-adrenoceptors or glucagon receptors. Our results thus indicate that apparently subtoxic neonatal chlorpyrifos exposure, devoid of effects on viability or growth but within the parameters of human fetal or neonatal exposures, produce a metabolic pattern for plasma lipids and insulin that resembles the major adult risk factors for atherosclerosis and type 2 diabetes mellitus.

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Figures

Figure 1

Figure 1

Effects of neonatal chlorpyrifos exposure on plasma lipids in adulthood. NS, not significant. Values shown are mean ± SE. ANOVA across all measures, feeding status, and sex appears at the top; data were subdivided into males and females because of the significant treatment × sex interaction. The main chlorpyrifos treatment effect for each sex is shown within the panel; separate lower-order tests for cholesterol or triglycerides in fed and fasted states were not carried out because of the absence of interactions of treatment × feeding status or treatment × lipid subtype. Note the different scales for cholesterol and triglycerides.

Figure 2

Figure 2

Effects of neonatal chlorpyrifos exposure on plasma glucose (A) and insulin (B) in adulthood. NS, not significant. Values shown are mean ± SE. ANOVA across feeding status and sex appears at the top of each panel. For insulin levels, lower-order analyses were run separately for males and females and for fed and fasted states because of the interaction of treatment with both feeding status and sex. Across both treatment groups, glucose and insulin levels were significantly lower in females than in males (main effect of sex, p < 0.002 for glucose, p < 0.0001 for insulin) and were reduced by fasting (main effect of feeding status, p < 0.0003 and p < 0.0001, respectively). *Significantly different from the corresponding control.

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