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Page 2 of 18 Monaco et al. J Environ Expo Assess 2024;3:18 https://dx.doi.org/10.20517/jeea.2024.10

differed from CON. Additionally, jejunal sucrase activity was higher in the DEHP200 than CON. Bacterial alpha
diversity differed significantly between DEHP groups and CON in the ascending colon, while beta diversity revealed
significant differences between DEHP200 and CON and DEHP20. The abundance of Christensenellaceae R-7 group,
Romboutsia, Lachnospiraceae UCG-004, Odoribacter, and Sphaerochaeta, among others, differed in DEHP-exposed vs.
CON animals. Thus, daily exposure to phthalates during infancy changes the villus structure and disaccharidase
activity in the small intestine and these changes may be modulated by the colonic bacterial community.

Keywords: Di-(2-ethylhexyl) phthalate, morphology, disaccharidase, microbiota, piglets

INTRODUCTION
Widespread exposure to environmental contaminants poses a significant concern for human health.
Epidemiological studies have reported associations between health outcomes and exposure to phthalates, a
ubiquitous plasticizer that gives plastics characteristic transparency and flexibility and is commonly utilized
[1]
in food packaging, personal care products, and medical devices . Phthalate exposure occurs through
ingestion, inhalation, dermal, and parenteral routes and has been linked to endocrine and reproductive
[2,3]
disruptions in humans and animals .
The time between conception and the first two years of life is critical for human development and is likely to
be the most sensitive period of the lifespan to environmental exposures . Indeed, epidemiological studies
[4]
have shown that pre- and postnatal exposure to environmental contaminants, including phthalates, are
associated with alterations in infant and toddler physical and behavioral development . In addition,
[5]
metabolic abnormalities, such as increased body weight (BW), atypical adipogenesis, energy expenditure,
and glucose metabolism, are observed in mice exposed to di-(2-ethylhexyl) phthalate (DEHP) prenatally or
in adulthood . Additionally, there is concern regarding the potential accumulation of toxicant
[6,7]
concentrations and an extended excretion period in infants during their early life stages due in part to their
[8,9]
immature capacity to detoxify environmental contaminants .
The primary sources of nutrition for infants in the first 6 months of life, human milk and infant formula,
are sources of environmental contaminants; phthalate metabolites are present in both human milk and
formula [10-12] . A recent study in Southern China found that breastfed infants had an estimated phthalate
intake between 0.383 to 6.95 µg/kg BW , which is below the tolerable daily intake of 50 µg/kg BW set by
[10]
[13]
the European Food Safety Authority . Infants and children are frequently exposed to other sources of
plasticizers present in bottles, toys, lotions, and, in some instances, medical devices. While some human
studies have reported detrimental developmental impacts of phthalate exposure during the early postnatal
period, a recent systematic review has concluded that quantitative evidence on the effects of exposure to
phthalates during this period is limited and studies have methodological limitations . Additionally, most
[14]
data on early-life phthalate exposure are derived from rodent studies.

The present study aimed to assess the phthalate-mediated early-life impact on the gastrointestinal tract in
the neonatal pig, a well-characterized biomedical model for human infants. The neonatal piglet has been
used extensively to understand the influence of environmental factors in the early developmental stages of
life due to its shared similarities in gastrointestinal anatomy and a closer similarity in gut microbiota
composition to humans than any other species [15,16] . Furthermore, the neonatal pig is a model for assessing
the interactions between microbiota and health, as it exhibits disorders similar to those in humans . The
[16]
DEHP dosages were selected based on previous work from our group, which has been shown to have long-
term detrimental effects on female reproductive health in mice [17,18] . We hypothesized that exposure to