In Utero Maternal 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 a 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 5 days/week (6h/day from gestational day 1 to birth) 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 displayed glucose and insulin intolerance, associated with elevated expression of hepatic gluconeogenesis and inflammatory genes. Additionally, this effect was accompanied by elevated insulin secretion and increased beta-cell mass only in male offspring. Thus, gestational benzene exposure can reprogram offspring for increased susceptibility to metabolic imbalance in adulthood with differential sensitivity between sexes.

Prenatal benzene exposure alters offspring hypothalamic development predisposing to metabolic disease in later life

“…3C). Thus, prenatal benzene exposure alters hypothalamic leptin signaling of male offspring, affecting the organization of neural circuits that regulate energy homeostasis and glucose metabolism, which may contribute to sex-specific metabolic alterations previously observed in this model (8).…”

“…Indeed, increased offspring risk for cardiovascular and metabolic disease later in life has also been described in the context of the altered maternal environment, such as GDM, obesity, and exposure to environmental toxic compounds during pregnancy (5–7). In support, we have recently shown that gestational exposure to benzene at the levels relevant to cigarette smoking, induces deleterious effects on energy homeostasis, hyperglycemia, and insulin resistance in adult offspring (8). However, the mechanisms underlying fetal metabolic programming and predisposition to metabolic imbalance following gestational exposure to benzene remain unknown.…”

“…Notably, cigarette smoke is the primary source of non-occupational benzene exposure in the US population (56, 57). We have recently demonstrated that in-utero exposure of pregnant female mice to benzene at concentrations relevant to smoking leads to altered energy homeostasis and glucose intolerance in the offspring, with a stronger effect in the male offspring (8). Here we demonstrate for the first time that a window of vulnerability exists during gestational development where the hypothalamus is especially sensitive to such exposure, causing irreversible damage to the hypothalamic nutrient and metabolic circuits, neuroinflammation, and alterations in the hypothalamic transcriptome, especially in male offspring.…”

“…Importantly, metabolic changes co-occur with changes in genes that affect CNS development and function, highlighting the susceptibility of the developing hypothalamus to environmentally-induced stress. These early changes in the genes profile in the hypothalamus might explain the stronger predisposition to the peripheral metabolic imbalance in benzene-exposed male offspring compared to females (8).…”

“…In the present study, we aimed to elucidate the impact of prenatal benzene exposure (at smoking levels (8)) on the offspring’s hypothalamic development and in response to the diet-induced obesity (DIO) challenge. Our data provide concrete evidence for the sex-specific effect of prenatal benzene exposure on the hypothalamic transcriptome, metabolic pathways, and neuroinflammation that can subsequently act as a driver for late-life metabolic disease.…”