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Table 2 Impact of TiO2 particles on intestinal epitheliuma

From: Titanium dioxide particles from the diet: involvement in the genesis of inflammatory bowel diseases and colorectal cancer

Study

Test system

Exposure conditions: dose range and exposure time

Material

Dispersion procedure

Main conclusions

Faust et al., 2014 [89]

Caco-2BBe1 cells, differentiated

Exposure using microgravity bioreactor (“floating” epithelia) for 24 h

E171 (anatase from XRD, 122 nm from TEM, “E171”) and E171 extracted from gum (141 nm, TEM, “gum E171”)

Probe sonication > 2 min, then dilution in exposure medium, then probe sonication > 2 min

Disruption of the brush border independently of particle sedimentation (in a microgravity reactor, or in inverted epithelium configuration): fewer microvilli, limp, less erected, at 350 ng/mL and 3.5 μg/mL of gum E171 or E171.

Brun et al., 2014 [52]

In vitro: differentiated Caco-2 and co-culture of Caco-2/HT29-MTX; ex vivo: Ussing chamber; in vivo: mice, oral gavage

In vitro: 50 μg/mL for 6 h, 24 h or 48 h; ex vivo: 50 μg/mL for 2 h; in vivo: 12.5 mg/kg b.w., sacrifice after 6 h

anatase (12 nm, TEM)

Probe sonication 30 min in water

In vitro: no impact on TEER value, paracellular and transcellular transport properties, activity of the P-gP. Upregulation of mRNA levels of proteins involved in tight and adherens junctions. In vivo and ex vivo: increased paracellular permeability after exposure to TiO2-NPs, downregulatio of mRNA expression of junction proteins (TJP1, TJP2, OCLN) in the ileum of mice exposed in vivo.

Dorier et al., 2015 [91]

Caco-2 cells, differentiated

50 μg/mL for 6 h, 24 h or 48 h

Anatase (12 nm, TEM) and rutile (20 nm, TEM)

 

Early and transient modulation of mRNA expression of ABC transporter genes, late modulation of mRNA expression of some SLC transporter genes. At 48 h significant increase of ABC transporter protein level (significant decrease at 4 h).

Guo et al., 2017 [92]

Co-culture of Caco-2/ HT29-MTX cells

106, 108 and 1010 particles/cm2 (low, medium, high concentration), for 4 h (acute) or 5 days (chronic)

TiO2-NPs, 20–40 nm from TEM

Suspension in water, mixing, no sonication

Chronic exposure decreased TEER value at the three doses (not acute), enlargement of the gaps between cells, as shown via OCLN protein immunostaining. Decreased Fe, Zn and fatty acid transport transport. mRNA expression of nutrient transporters affected.

Li et al., 2018 [61]

Mice (10 mice per group), oral gavage

100 mg/kg b.w./day, once a day for 28 days

Anatase (20 nm, DLS) and rutile (16 nm, DLS)

Suspension in distilled water, no sonication

Longer intestinal villi in the colon (mild effect) and disturbed arrangement of villus epithelial cells when exposed to rutile but not anatase.

Jensen et al., 2019 [134]

Rats, oral gavage once a week during 10 weeks

50 μg/kg b.w./week (low dose) and 500 μg/kg b.w./week (high dose)

E171 (anatase, sizes: 135 nm, 305 nm and 900 nm from TEM)

Indirect cup-type sonication (high energy) in 2% FBS, 16 min

Decreased mRNA expression of TJP1 in the colon mucosa at the high dose.

Dorier et al., 2019 [95]

Differentiated Caco-2 and co-culture of Caco-2/HT29-MTX

Repeated exposure (twice a week for 21 days); 10 and 50 μg/mL

E171 (anatase, 119 nm), A12 (anatase, 12 nm), NM105 (anatase/rutile, 21 nm)

Indirect cup-type sonication (high energy) in water, 30 min

No perturbation of the in vitro epithelial barrier development over the 21 days of exposure: TEER, mRNA expression of junction proteins and markers of microvilli differentiation unaffected. Decreased (E171) or decreased (NM105) levels of ABC transporters when repeated exposure.

Pinget et al., 2019 [133]

Mice, drinking water

2, 10, 50 mg TiO2/kg b.w./day for 21 days

E171

Suspension in drinking water

No impact on Tjp1 expression, suggesting no impact on intestinal permeability. Expression of Defb3, encoding beta-defensin 3, increased; granzyme B, cathelin-related antimicrobial peptide, regenerating islet-derived protein 3 gamma and p-lysozyme not significantly modulated. Reduction of colonic crypt length at 50 mg/kg b.w./day, no impact on colon length.

Talamini et al., 2019 [21]

Mice, TiO2 dripped into the mouse’s mouth

~ 2 mg/kg b.w./day 3 days/week for 3 weeks

E171

Suspension in water, no sonication, dripped into the mouth

No overt structural or morphological alteration in the stomach and intestine, no disruption of crypt structure, no atypical cell proliferation.

Medina-Reyes et al., 2020 [88]

Mice with either high fat diet (HFD) or regular diet (RD)

5 mg/kg b.w. for 16 weeks

E171

Suspension in drinking water

Decreased colon crypt length, as compared to the respective control (HFD or RD).

Zhang et al., 2021 [90]

Mice

1% w/w TiO2 for 1, 3 or 6 months

 

TiO2 incorporated in food pellets

Increased villi height/crypt depth ratios at 1 and 3 months; increased expression of ZO-1 and occludin at 1 month; spare microvilli in small intestine at 6 months. No change in intestinal permeability.

  1. aAbbreviations: ABC ATP-binding cassette, FBS foetal bovine serum, OCLN occludin, SLC solute liquid carrier, TEER transepithelial resistance, TEM transmission electron microscopy, TJP tight junction protein, XRD X-ray diffraction