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Gestational Cd exposure in the CD-1 mouse induces sex-specific hepatic insulin insensitivity, obesity and metabolic syndrome in adult female offspring

Jackson, Thomas; Ryherd, Garret; Scheibly, Chris; Sasser, Aubrey; Guillette, T. C.; Belcher, Scott

There is compelling evidence that developmental exposure to some toxic metals increases risk for obesity and obesity-related morbidity including cardiovascular disease and type 2 diabetes in adults. To explore the hypothesis that developmental Cd exposure increased 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 (GD0 - PND10). Hallmark indicators of metabolic disruption, hepatic steatosis, and metabolic syndrome were evaluated prior to birth through adulthood. Blood Cd levels in dams were similar to those observed in human pregnancy cohorts. 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 glucose homeostasis in young adult offspring. Exposure-related increases in circulating triglycerides and hepatic steatosis were apparent only in females. By PND120, Cd-exposed females had become 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 at 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.

Funding provided by: National Institute of Environmental Health Sciences
Crossref Funder Registry ID: http://dx.doi.org/10.13039/100000066
Award Number: 5T32ES007046-38

Funding provided by: National Institute of Environmental Health Sciences
Crossref Funder Registry ID: http://dx.doi.org/10.13039/100000066
Award Number: P30ES025128

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Supplemental_Table_S4_PND42_GoTerm.xlsx
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Supplemental_Table_S8_PND21_GoTerm.xlsx
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