Just recently I had a customer who had to send newsletters generated from a custom application. All e-mails were relayed through their Exchange 2010 server. The problem was that all bounced e-mails not delivered for various reasons were returned to the sender's address. The customer tried to modify Return-path header from the application side so that all bounced e-mails would be returned to a special mailbox from which returned e-mails could be parsed and analyzed.
The problem is that Exchange does not accept Return-path from a client but it automatically applies it to the message using the From header. The solution for the problem is very simple and that is to generate e-mail message with Sender and From fields. The Sender field should be populated with the "bounce-back" e-mail address and the From field with the e-mail address that final recipient should see as a sender of the message. Exchange will then populate the Return-path variable using the Sender field instead of From field.
You can test with this simple powershell script:
$smtpServer = "some_ip_address"
$msg = new-object Net.Mail.MailMessage
$smtp = new-object Net.Mail.SmtpClient($smtpServer)
$msg.From = "email@example.com"
$msg.Sender = "firstname.lastname@example.org"
$msg.Subject = "Email Test"
$msg.Body = "Testing return-path header"