Maternal exposure to titanium dioxide nanoparticles during pregnancy and lactation alters offspring hippocampal mRNA BAX and Bcl-2 levels, induces apoptosis and decreases neurogenesis

Exp Toxicol Pathol. 2017 Jul 5;69(6):329-337. doi: 10.1016/j.etp.2017.02.006. Epub 2017 Feb 27.


Introduction: The usage of Titanium dioxide nanoparticles (TiO2-NPs) covers a vast area in different fields ranging from cosmetics and food to the production of drugs. Maternal exposure to TiO2-NPs during developmental period has been associated with hippocampal injury and with a decrease in learning and memory status of the offspring. However, little is known about its injury mechanism. This paper describes the in vivo neurotoxic effects of TiO2-NPs on rat offspring hippocampus during developmental period.

Material and methods: Pregnant and lactating Wistar rats received intragastric TiO2-NPs (100mg/kg body weight) daily from gestational day (GD) 2 to (GD) 21 and postnatal day (PD) 2 to (PD) 21 respectively. Animals in the control groups received an equal volume of distilled water via gavage. At the end of the treatment process, offspring were deeply anesthetized and sacrificed. Then brains of each group were collected and sections of the rat offspring's brains were stained using TUNEL staining (for detection of apoptotic cells) and immunostaining (for neurogenesis). Moreover, the right hippocampus (n=6 per each group) were removed from the right hemisphere for evaluating the expression of Bax and Bcl-2 level.

Results: Results of histopatological examination by TUNEL staining showed that maternal exposure to TiO2-NPs during pregnancy and lactation periods increased apoptotic cells significantly (P<0.01) in the offspring hippocampus. The immunolabeling of double cortin (DCX) protein as neurogenesis marker also showed that TiO2-NPs reduced neurogenesis in the hippocampus of the offspring (P<0.05). Moreover, in comparison with the control group, the mRNA levels of Bax and Bcl-2 in the TiO2-NPs group significantly increased and decreased, respectively (P<0.01).

Conclusion: These findings provide strong evidence that maternal exposure to TiO2-NPs significantly impact hippocampal neurogenesis and apoptosis in the offspring. The potential impact of nanoparticle exposure for millions of pregnant mothers and their offspring across the world is potentially devastating.

Keywords: Apoptosis; Hippocampus; Maternal exposure; Neurogenesis; Titanium dioxide nanoparticles.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Doublecortin Protein
  • Female
  • Hippocampus / drug effects*
  • Hippocampus / pathology
  • Lactation
  • Maternal Exposure / adverse effects*
  • Metal Nanoparticles / toxicity*
  • Neurogenesis / drug effects*
  • Pregnancy
  • Prenatal Exposure Delayed Effects / pathology
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis
  • Proto-Oncogene Proteins c-bcl-2 / drug effects
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / drug effects
  • Rats
  • Rats, Wistar
  • Titanium / toxicity*
  • bcl-2-Associated X Protein / biosynthesis
  • bcl-2-Associated X Protein / drug effects


  • Dcx protein, rat
  • Doublecortin Protein
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Messenger
  • bcl-2-Associated X Protein
  • titanium dioxide
  • Titanium