Persistent impact of in utero nanoparticle exposure on metabolic and endocrine outcomes in adult rats fed a high-fat diet

Gestational nano titanium-dioxide (nano-TiO₂) exposure causes reduced fetal size and multi-generational reproductive effects in females. The current study utilized a whole-body nano-TiO₂ inhalation exposure model in pregnant Sprague-Dawley rats coupled with a high fat diet (HFD) fed to adult offspring to examine lasting effects of in-utero exposures on weight gain, metabolic function, and endocrine perturbations. Sexually dimorphic responses in weight gain were observed whereby exposed HFD males gained less weight than their air HFD counterparts (435 g ± 9.8 vs. 505 g ± 14.5; p < 0.05), but there was no weight difference between air and exposed HFD females. Males and females presented with exposure driven decreases in glucose tolerance, such that HFD exposed animals were significantly more glucose intolerant(-6985AUC±1763). Hypothalamic gene expression of the melanocortin receptor 3 was significantly increased in nano-TiO₂ males (1453 %) and significantly decreased in nano-TiO₂ females (29.07 %) compared to grain-based diet (GBD) controls. Hepatic mitochondrial activity was affected in sexually dependent manner, with females exhibiting changes in Complexes I, II, III, and V, and males only showing differences in Complex I activity. Finally, exposed males had smaller testicular mass (3.685 mg ± 0.0895 in GBD; 3.358 mg±0.0786 in HFD; (3.480 mg± 0.2023 in GBD, 3.380 mg± 0.0777) and reduced testosterone (7.75 µg/nl ± 1.965 in GBD; 3.62 µg/nl±2.084 in HFD; (9.943 µg/nl±1.97 in GBD, 4.28 µg/nl± 1.6845) compared to air males. Altogether, these data reflect how nanoparticulate driven differences in growth and development at birth can alter weight gain and metabolic function later in life in the face of a dietary challenge.