In UteroMaternal Benzene Exposure Predisposes to the Metabolic Imbalance in the Offspring

Abstract

Environmental chemicals play a significant role in the development of metabolic disorders, especially when exposure occurs early in life. We have recently demonstrated that benzene exposure, at concentrations relevant to cigarette smoke, induces a severe metabolic imbalance in a sex-specific manner affecting male but not female mice. However, the roles of benzene in the development of aberrant metabolic outcomes following gestational exposure, remain largely unexplored. In this study, we exposed pregnant C57BL/6JB dams to benzene at 50 ppm or filtered air for 6 h/day from gestational day 0.5 (GD0.5) through GD21 and studied male and female offspring metabolic phenotypes in their adult life. While no changes in body weight or body composition were observed between groups, 4-month-old male and female offspring exhibited reduced parameters of energy homeostasis (VO2, VCO2, and heat production). However, only male offspring from benzene-exposed dams were glucose intolerant and insulin resistant at this age. By six months of age, both male and female offspring exhibited marked glucose intolerance however, only male offspring developed severe insulin resistance. This effect was accompanied by elevated insulin secretion and increased beta-cell mass only in male offspring. In support, HOMA-IR, the index of insulin resistance was elevated only in male but not in female offspring. Regardless, both male and female offspring exhibited a considerable increase in hepatic gene expression associated with inflammation and ER stress. Thus, gestational benzene exposure can predispose offspring to increased susceptibility to the metabolic imbalance in adulthood with differential sensitivity between sexes.

Prenatal Pollutant Exposures and Hypothalamic Development: Early Life Disruption of Metabolic Programming

“…However, only male offspring of DEP-exposed dams exhibited exaggerated weight gain, insulin resistance, and anxiety-like behavior when challenged with HFD compared with male control offspring ( 69 ). In support, we have previously demonstrated that maternal exposure to inhaled benzene throughout pregnancy was associated with hyperglycemia, insulin resistance, reduced energy expenditure, and increased hepatic inflammation in the adult male offspring ( 73 ). Similarly, exposure to benzene in adulthood was also associated with a metabolic imbalance in male but not female mice ( 74 ).…”

“…In support, we have previously demonstrated that maternal exposure to inhaled benzene throughout pregnancy was associated with hyperglycemia, insulin resistance, reduced energy expenditure, and increased hepatic inflammation in the adult male offspring (73). Similarly, exposure to benzene in adulthood was also associated with a metabolic imbalance in male but not female mice (74).…”

“…As the onset of metabolic disorders steadily increases in children and young adults, there is a great need to understand this etiology. Significant associations have been found between prenatal exposure to environmental pollutants and the heightened risk for metabolic impairments ( 69 , 71 , 73 , 125 ). One potential mechanism is an increase in neuroinflammation, particularly affecting the hypothalamus.…”

Sex Difference and Benzene Exposure: Does It Matter?

“…With regard to prenatal exposure, Koshko et al, demonstrated that benzene induce metabolic perturbation (energy homeostasis and glucose metabolism), more severe in male offspring than in females [ 53 ].…”

“…Prenatal exposure in in vivo experiments demonstrated that benzene could cross the placenta and reach the fetus, and different sex-based effects were observed [ 53 ]. In agreement with the greater susceptibility of males to benzene effects, male fetuses appeared more vulnerable to oxidative stress caused by benzene exposure [ 56 ] while adult male offspring developed insulin resistance [ 53 ]. In addition, offspring showed a trend of higher development of hepatic tumors in males and hematopoietic tumors in females.…”