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Page 12 of 18 Monaco et al. J Environ Expo Assess 2024;3:18 https://dx.doi.org/10.20517/jeea.2024.10

exposure. Although infants may not metabolize or eliminate phthalate byproducts as effectively as adults in
[9]
the first 6 months of life, this capacity evolves over time .
In contrast to findings in rodents [7,45] , exposure to DEHP at 20 or 200 mg/kg did not affect BW gain or organ
size in pigs. However, significant changes in intestinal morphology and function were observed. The highest
DEHP dose was associated with shorter villi but deeper crypts in the jejunum compared to CON, indicating
villus atrophy and crypt hyperplasia. Comparable outcomes were noted in adult mice receiving a high dose
(500 mg/kg BW) of dibutyl phthalate (DBP) . In this investigation, the DBP-treated group had
[46]
significantly reduced jejunal villus height and villus/crypt ratio compared to the control group, with no
notable changes in crypt depth. Conversely, DBP administration had the opposite effect in the duodenum,
leading to a significant increase in villus height and villus/crypt ratio . Likewise, a study of quails exposed
[47]
to high levels of DEHP (250, 500, 750 mg/kg BW) reported decreased villi length and increased crypt depth
in the duodenum. As a result of the exposure, disruption of the epithelial barrier and varying degrees of
[47]
intestinal inflammation were observed . Diisononyl phthalate (DINP) fed to female rats during pregnancy
and lactation caused severe villous atrophy in the 30-day-old offspring, while DEHP administration resulted
in intestinal lymphoepithelial lesions . The same study documented higher lactase and sucrase activities in
[48]
the small intestine. Similarly, we noted a DEHP dose-dependent increase in sucrase activity in the jejunum,
[49]
while no discernible impact of DEHP was observed in the duodenum and ileum. Beumer and Clevers
presented new insights into stem cell regulation and fate specification in response to intestinal insults or
damage. They postulated that cells in the intestinal epithelium have a certain degree of plasticity that allows
them to function as stem cells and display context-dependent functionality as dictated by their
microenvironment. Others have hypothesized that the gut microbiota may modulate changes in intestinal
function and structure after an insult such as DEHP exposure [50,51] .

Many intestinal responses to environmental factors are associated with and modulated by the composition
and diversity of the colonic microbiota. The establishment of the gut microbiota starts at birth and evolves
during childhood until it reaches a composition that resembles those found in adults . Microbial dysbiosis
[52]
during early life has the potential to lead to chronic diseases, including inflammatory bowel disease, asthma,
[53]
and obesity, among others . In recent years, environmental chemicals have been shown to alter the
microbiota. This study is the first, to our knowledge, to describe the significant effects of DEHP on the
microbiota in young pigs. Others demonstrated that exposure to bisphenol A (BPA) at the concentration of
500 mg/kg BW/day (or 0.1% in the diet) resulted in impaired growth performance and intestinal
morphology but observed no differences in alpha and beta diversity in young pigs . In our study, bacterial
[54]
richness (observed features and Shannon indices) increased significantly in the AC regardless of the DEHP
dose, with no differences detected in the RC. Furthermore, differences in overall bacterial communities
(beta diversity) separated the microbiota of animals from the high level of exposure from control and low
level. Studies in pubertal female mice observed increased fecal alpha diversity (Chao1 index) after 7 days of
[55]
oral administration of 1 or 10 mg DEHP/kg BW/day . The effect disappeared after 14 days of treatment. In
contrast, the work by Cheng et al. showed a significant decrease in microbial richness and structure in 6-
week-old male C57BL/6 mice receiving 1,000 mg DEHP/kg BW/day for 15 weeks relative to non-exposed
mice . However, microbial diversity between control and animals exposed to 200 and 500 mg/kg BW/day
[56]
did not differ.

To further explore the effect of DEHP on the composition of the microbiota, differential analyses at phylum
and genus levels were performed. The distribution of bacteria at the phylum level did not differ between
CON and DEHP20. DEHP200 led to significant changes in the abundance of Bacillota and Bacteroidota in
[57]
the AC, which account for 90% of the sequences annotated in the colon content of young pigs . The overall