P-550 Transgenerational epigenetic influences of maternal circadian rhythm changes during pregnancy and lactation periods on cognition and behavior in male offspring
Authors: Sati L , Tas G.G , Zengin G , Cakmakli U , Denizalti T , Sahin P , Derin N 
Published: June 2022

Abstract

Study question
Do maternal circadian rhythm changes during pregnancy and lactation periods cause transgenerational behavioral and cognitive alterations in male offspring?

Summary answer
Maternal circadian rhythm changes cause impaired behavioral alterations such as motor activity impairments, increased anxiety and weakening of spatial memory in male offspring.

What is known already
The circadian system regulates the daily temporal organization in behavior and physiology in most species. Recent publications in model systems have emphasized the negative effects of circadian rhythm disruption on both female and male reproduction and fertility. There is growing concern about the long-term effects of circadian rhythm disruptions during pregnancy and lactation periods on human offspring and their descendants as circadian regulation during these periods can potentially alter epigenetic programing in offspring. However, there is a lack of information about the possible transgenerational effects of circadian rhythm disorders for the health of offspring in the literature.

Study design, size, duration
Male offspring from pregnant Wistar rats (n = 60) which were exposed to control (12 hours light/12 hours dark), short day (SD) (8 hours light/16 hours dark) or long day (LD) periods (16 hours light/8 hours dark) during only pregnancy, only lactation or both periods (n = 15/group) categorized as control, SD pregnancy (SD-P), SD lactation (SD-L), SD pregnancy and lactation (SD-P+L), LD pregnancy (LD-P), LD lactation (LD-L), LD pregnancy and lactation (LD-P+L) groups.

Participants/materials, setting, methods
The length of gestation, litter size, sex ratio of pups (fraction male) and birth weights were recorded. The maternal locomotor activity and anxiety were analyzed by open field (OF) and elevated plus maze (EPM) tests, respectively (n = 15 mothers/group). Learning and memory, locomotor activity and anxiety related changes were studied in the male offspring in pre-pubertal, pubertal and adult periods with object localization (OL) and Morris water maze (MWM), OF and EPM tests, respectively.

Main results and the role of chance
Newborn weights was significantly increased in SD (5.01±0.07) and LD (4.47±0.29) groups compared to control group (3.73±0.03) (p &lt; 0.001). Male sex ratio of pups born to mothers on SD schedule was unusually low (0.21±0.62) compared to mothers on normal light schedule (0.48±0.05) (p &lt; 0.001). The gestation length was not altered. Locomotor activity was increased in mothers exposed to SD schedule (p &lt; 0.01). A significant motor activity impairment in the prepubertal period was remarkable in SD-P+L, LD-P, LD-L and LD-P+L groups (p &lt; 0.001). Compared to control group, EPM test showed that all the offspring in SD groups had significant increase in their anxiety in the prepubertal period. Motor functions that decreased before puberty seems gradually improved at adulthood. Weakened short-term spatial memory was observed at puberty, especially in SD-P (p &lt; 0.001), SD-P+L (p &lt; 0.05), LD-P (p &lt; 0.05) groups. Time to find the platform was significantly higher than those measured for control group for SD-P-L (p &lt; 0.001) in the prepubertal period and LD-P+L group (p &lt; 0.001) in the pubertal period meaning decreased spatial memory and learning. A probe trial given on day 6 with MWM test showed that LD groups had no alterations in spatial memory whereas SD-P (p &lt; 0.05) and SD-G+L (p &lt; 0.001) groups showed impaired changes in long-term spatial memory.

Limitations, reasons for caution
Due to limitations of working with human subjects exposed to shift work schedules, most chronoregulation research including ours has used rodent models with limitations in translating to human studies. However, to truly know if such concerns apply to humans will require retrospective and prospective human studies.

Wider implications of the findings
Epigenetic transitions are crucial for transcriptional reprogramming triggered by environmental cues. Our study might provide valuable information regarding transgenerational effects of maternal chronodisruption on health later in life of the offspring, particularly at prepubertal and pubertal periods, create suggestions and guidelines for reproductive biology, shift work and possible infertility problems.

Trial registration number
This work was supported by research grants from the Scientific and Technological Research Council of Turkey (TUBITAK) (SBAG 219S636) and Akdeniz University, The Scientific Research Projects Coordination Unit (TYL-2018-3580).