Gestational Cd Exposure in the CD-1 Mouse Induces Sex-Specific Hepatic Insulin Insensitivity, Obesity, and Metabolic Syndrome in Adult Female Offspring

Abstract

There is compelling evidence that developmental exposure to toxic metals increases risk for obesity and obesity-related morbidity including cardiovascular disease and type 2 diabetes. To explore the hypothesis that developmental Cd exposure increases risk of obesity later in life, male, and female CD-1 mice were maternally exposed to 500 ppb CdCl2 in drinking water during a human gestational equivalent period (gestational day 0-postnatal day 10 [GD0-PND10]). Hallmark indicators of metabolic disruption, hepatic steatosis, and metabolic syndrome were evaluated prior to birth through adulthood. Maternal blood Cd levels were similar to those observed in human pregnancy cohorts, and Cd was undetected in adult offspring. There were no observed impacts of exposure on dams or pregnancy-related outcomes. Results of glucose and insulin tolerance testing revealed that Cd exposure impaired offspring glucose homeostasis on PND42. Exposure-related increases in circulating triglycerides and hepatic steatosis were apparent only in females. By PND120, Cd-exposed females were 30% heavier with 700% more perigonadal fat than unexposed control females. There was no evidence of dyslipidemia, steatosis, increased weight gain, nor increased adiposity in Cd-exposed male offspring. Hepatic transcriptome analysis on PND1, PND21, and PND42 revealed evidence for female-specific increases in oxidative stress and mitochondrial dysfunction with significant early disruption of retinoic acid signaling and altered insulin receptor signaling consistent with hepatic insulin sensitivity in adult females. The observed steatosis and metabolic syndrome-like phenotypes resulting from exposure to 500 ppb CdCl2 during the pre- and perinatal period of development equivalent to human gestation indicate that Cd acts developmentally as a sex-specific delayed obesogen.

Gestational Cd Exposure in the CD-1 Mouse Sex-Specifically Disrupts Essential Metal Ion Homeostasis

“…For example, adult Cd exposure induces anemia by altering iron metabolism and homeostasis, whereas increased pregnancy and lactation Cd levels associated with Fe deficiency (Akesson et al 2002; Horiguchi et al 2011). We also observed anemia at birth in newborn mice following maternal exposure to 500 ppb CdCl 2 , a find that suggests iron concentrations were altered by gestational exposure to relatively low Cd concentrations (Jackson et al 2020).…”

“…In our previous study, compared to unexposed controls, Cd exposure resulted in a small but significant 5.5 % increase in the female GD18 fetus weight, whereas male fetus weight was unchanged (Jackson et al 2020). Here, exposed male, but not female GD18 placenta weight was increased by 22% leading to a 15% decline in placental efficiency.…”

“…The primary study findings were that sex-specific adverse metabolic effects of gestational Cd exposure observed previously were associated with increased transplacental Cd transfer from dam to female offspring, with subsequent Cd accumulation in female liver. It is considered probable that Cd accumulation is programming female offspring for hepatic dysfunction, resulting in the adverse metabolic disruption observed in adult females (Jackson et al 2020). In our previous study we demonstrated that maternal blood Cd levels of exposed dams at mating was similar to geometric mean blood Cd concentrations for women of childbearing age in the US.…”

“…All animal procedures were carried out as previously described (Jackson et al 2020) following recommendations of the Panel on Euthanasia of the American Veterinary Medical Association, and were approved by the North Carolina State University Institutional Animal Care and Use Committee. Study animals were housed in single-use polyethylene cages (Innovive, San Diego, CA) with Sanichip bedding (PJ Murphy Forest Products Corp, Montville, NJ) and pulped virgin cotton fiber nestlets (Ancare, Bellmore, NY) on a 12:12 light cycle at 25°C and 45%-60% average relative humidity in an AAALAC accredited animal facility.…”

“…Emerging data suggests developmental Cd exposure increases risk for childhood obesity (King et al 2015; Lamas et al 2016). Using a mouse model of human gestational Cd exposure, we previously demonstrated that Cd body burdens equivalent to women of childbearing age sex-specifically caused hepatic steatosis, dyslipidemia, glucose intolerance, insulin resistance, and obesity in female offspring (Jackson et al 2020). The resulting later-in-life obesogenic effects of gestational Cd exposure in females were found to be mediated by well-established mechanisms involved in cumulative Cd toxicity (Sabolić et al 2010; Nair et al 2013; Nemmiche 2016 Nov 1).…”