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Neonatal nicotine exposure affects adult rat hepatic pathways involved in endoplasmic reticulum stress and macroautophagy in a sex-dependent manner

Published online by Cambridge University Press:  01 December 2023

Luana Lopes Souza ,
Camila Lüdke Rossetti ,
Thamara Cherem Peixoto ,
Alex Christian Manhães Open the ORCID record for Alex Christian Manhães [Opens in a new window] ,
Egberto Gaspar de Moura Open the ORCID record for Egberto Gaspar de Moura [Opens in a new window]  and
Patrícia Cristina Lisboa Open the ORCID record for Patrícia Cristina Lisboa [Opens in a new window]
Luana Lopes Souza
Affiliation:
Laboratory of Endocrine Physiology, Biology Institute, State University of Rio de Janeiro, Rio de Janeiro, Brazil
Camila Lüdke Rossetti
Affiliation:
Laboratory of Endocrine Physiology, Biology Institute, State University of Rio de Janeiro, Rio de Janeiro, Brazil
Thamara Cherem Peixoto
Affiliation:
Laboratory of Endocrine Physiology, Biology Institute, State University of Rio de Janeiro, Rio de Janeiro, Brazil
Alex Christian Manhães
Affiliation:
Laboratory of Neurophysiology, Biology Institute, State University of Rio de Janeiro, Rio de Janeiro, Brazil
Egberto Gaspar de Moura
Affiliation:
Laboratory of Endocrine Physiology, Biology Institute, State University of Rio de Janeiro, Rio de Janeiro, Brazil
Patrícia Cristina Lisboa*
Affiliation:
Laboratory of Endocrine Physiology, Biology Institute, State University of Rio de Janeiro, Rio de Janeiro, Brazil
*
Corresponding author: P. C. Lisboa; Email: pclisboa.uerj@yahoo.com.br
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Abstract

Nonalcoholic fatty liver disease (NAFLD) involves changes in hepatic pathways, as lipogenesis, oxidative stress, endoplasmic reticulum (ER) stress, and macroautophagy. Maternal nicotine exposure exclusively during lactation leads to fatty liver (steatosis) only in the adult male offspring, not in females. Therefore, our hypothesis is that neonatal exposure to nicotine sex-dependently affects the signaling pathways involved in hepatic homeostasis of the offspring, explaining the hepatic lipid accumulation phenotype only in males. For this, between postnatal days 2 and 16, Wistar rat dams were implanted with osmotic minipumps, which released nicotine (NIC; 6 mg/Kg/day) or vehicle. The livers of offspring were evaluated at postnatal day 180. Only the male offspring that had been exposed to nicotine neonatally showed increased protein expression of markers of unfolded protein response (UPR), highlighting the presence of ER stress, as well as disruption of the activation of the macroautophagy repair pathway. These animals also had increased expression of diacylglycerol O-acyltransferase 1 and 4-hydroxynonenal, suggesting increased triglyceride esterification and oxidative stress. These parameters were not altered in the female offspring that had been neonatally exposed to nicotine, however they exhibited increased phospho adenosine monophosphate-activated protein kinase pAMPK expression, possibly as a protective mechanism. Thus, the disturbance in the hepatic homeostasis by UPR, macroautophagy, and oxidative stress modifications seem to be the molecular mechanisms underlying the liver steatosis in the adult male offspring of the nicotine-programming model. This highlights the importance of maternal smoking cessation during breastfeeding to decrease the risk of NAFLD development, especially in males.

Keywords

Lactationnicotinedevelopmental programmingsexual dimorphismliver homeostasis
Type
Original Article
Information
Journal of Developmental Origins of Health and Disease , Volume 14 , Issue 5 , October 2023 , pp. 639 - 647
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Copyright
© The Author(s), 2023. Published by Cambridge University Press in association with The International Society for Developmental Origins of Health and Disease (DOHaD)

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